Compounds and compositions as lxr modulators

ABSTRACT

The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of liver X receptors (LXRs).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of application Ser. No.10/589,087, filed 10 Aug. 2006, which is a 371 U.S. national phaseapplication of international application number PCT/US2005/004655 filed11 Feb. 2005, which claims the benefit of U.S. Provisional ApplicationNo. 60/543,848, filed 11 Feb. 2004 and U.S. Provisional Application No.60/623,021, filed 27 Oct. 2004. The full disclosures of theseapplications are incorporated herein by reference in their entirety forall purposes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention provides compounds, pharmaceutical compositions comprisingsuch compounds and methods of using such compounds to treat or preventdiseases or disorders associated with the activity of liver X receptors(LXRs).

2. Background

Liver X receptors (LXRs), LXRα and LXRβ, are nuclear receptors thatregulate the metabolism of several important lipids, includingcholesterol and bile acids. While LXRβ is expressed ubiquitously in thebody, LXRα is expressed in the liver and to a smaller degree in thekidneys, small intestine, adipose tissue, spleen and adrenal glands.

LXRs bind to the ATP binding cassette transporter-1 (ABCA1) promoter andincrease expression of the gene to produce ABCA1 protein. ABCA1 is amembrane bound transport protein that is involved in the regulation ofcholesterol efflux from extra-hepatic cells onto nascent high-densitylipoprotein (HDL) particles. Mutations in the ABCA1 gene result in lowlevels of HDL and an accompanying increased risk of cardiovasculardiseases such as atherosclerosis, myocardial infarction and ischemicstroke. LXRα and 13 agonists have been shown to increase ABCA1 geneexpression thereby increasing HDL cholesterol and, as a consequence,decreasing both the net absorption of cholesterol and the risk ofcardiovascular disease. LXR agonists also upregulate macrophageexpression of apolipoprotein E (apoE) and ABCG1, both of whichcontribute to the efflux of cellular cholesterol. By stimulatingmacrophage cholesterol efflux through upregulation of ABCA1, ABCG1and/or apoE expression, as well as increasing the expression of othertarget genes including cholesterol ester transfer protein andlipoprotein lipase, LXR agonists influence plasma lipoproteins.

The novel compounds of this invention modulate the activity of LXRs andare, therefore, expected to be useful in the treatment of LXR-associateddiseases such as cardiovascular diseases, inflammation and disorders ofglucose metabolism such as insulin resistance and obesity.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of Formula I:

in which:

-   -   n is selected from 0, 1, 2 and 3;    -   Z is selected from C and S(O); each    -   Y is independently selected from —CR₄═ and —N═; wherein R₄ is        selected from hydrogen, cyano, hydroxyl, C₁₋₆alkyl, C₁₋₆alkoxy,        halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy;    -   R₁ is selected from halo, cyano, hydroxyl, C₁₋₆alkyl,        C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl,        halo-substituted-C₁₋₆alkoxy and —C(O)OR₄; wherein R₄ is as        described above;    -   R₂ is selected from C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl        and C₃₋₈heterocycloalkyl; wherein any aryl, heteroaryl,        cycloalkyl or heterocycloalkyl of R₂ is optionally substituted        with 1 to 5 radicals independently selected from halo, hydroxy,        cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl,        halo-substituted-C₁₋₆alkoxy, —C(O)NR₅R₅, —OR₅, —OC(O)R₅, —NR₅R₆,        —C(O)R₅ and —NR₅C(O)R₅; wherein R₅ and R₆ are independently        selected from hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy,        halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,        C₆₋₁₀aryl-C₀₋₄alkyl, C₃₋₈heteroaryl-C₀₋₄alkyl,        C₃₋₁₂cycloalkyl-C₀₋₄alkyl and C₃₋₈heterocycloalkyl-C₀₋₄alkyl; or        R₅ and R₆ together with the nitrogen atom to which R₅ and R₆ are        attached form C₅₋₁₀heteroaryl or C₃₋₈heterocycloalkyl; wherein        any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₅ or        the combination of R₅ and R₆ is optionally substituted with 1 to        4 radicals independently selected from halo, hydroxy, cyano,        nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and        halo-substituted-C₁₋₆alkoxy;    -   R₃ is selected from C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl        and C₃₋₈heterocycloalkyl; wherein any aryl, heteroaryl,        cycloalkyl or heterocycloalkyl of R₃ is substituted with 1 to 5        radicals independently selected from halo, C₁₋₆alkoxy,        halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —OXR₇,        —OXC(O)NR₇R₈, —OXC(O)NR₇XC(O)OR₈, —OXC(O)NR₇XOR₈,        —OXC(O)NR₇XNR₇R₈, —OXC(O)NR₇XS(O)₀₋₂R₈, —OXC(O)NR₇XNR₇C(O)R₈,        —OXC(O)NR₇XC(O)XC(O)OR₈, —OXC(O)NR₇R₉, —OXC(O)OR₇, —OXOR₇,        —OXR₉, —XR₉, —OXC(O)R₉, —OXS(O)₀₋₂R₉ and —OXC(O)NR₇CR₇[C(O)R₈]₂;    -   wherein        -   X is a selected from a bond and C₁₋₆alkylene wherein any            methylene of X can optionally be replaced with a divalent            radical selected from C(O), NR₇, S(O)₂ and O;        -   R₇ and R₈ are independently selected from hydrogen, cyano,            C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl, C₂₋₆alkenyl and            C₃₋₁₂cycloalkyl-C₀₋₄alkyl; R₉ is selected from            C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl-C₀₋₄alkyl,            C₃₋₁₂cycloalkyl-C₀₋₄alkyl and            C₃₋₈heterocycloalkyl-C₀₋₄alkyl; wherein any alkyl of R₉ can            have a hydrogen replaced with —C(O)OR₁₀; and any aryl,            heteroaryl, cycloalkyl or heterocycloalkyl of R₉ is            optionally substituted with 1 to 4 radicals independently            selected from halo, C₁₋₆alkyl, C₃₋₁₂cycloalkyl,            halo-substituted-C₁₋₆alkyl, C₁₋₆alkoxy,            halo-substituted-C₁₋₆alkoxy, —XC(O)OR₁₀, —XC(O)R₁₀,            —XC(O)NR₁₀R₁₀, —XS(O)₀₋₂NR₁₀R₁₀ and —XS(O)₀₋₂R₁₀; wherein            R₁₀ is independently selected from hydrogen and C₁₋₆alkyl;    -   and the N-oxide derivatives, prodrug derivatives, protected        derivatives, individual isomers and mixture of isomers thereof;        and the pharmaceutically acceptable salts and solvates (e.g.        hydrates) of such compounds.

In a second aspect, the present invention provides a pharmaceuticalcomposition which contains a compound of Formula I or a N-oxidederivative, individual isomers and mixture of isomers thereof; or apharmaceutically acceptable salt thereof, in admixture with one or moresuitable excipients.

In a third aspect, the present invention provides a method of treating adisease in an animal in which modulation of LXR activity can prevent,inhibit or ameliorate the pathology and/or symptomatology of thediseases, which method comprises administering to the animal atherapeutically effective amount of a compound of Formula I or a N-oxidederivative, individual isomers and mixture of isomers thereof, or apharmaceutically acceptable salt thereof.

In a fourth aspect, the present invention provides the use of a compoundof Formula I in the manufacture of a medicament for treating a diseasein an animal in which LXR activity contributes to the pathology and/orsymptomatology of the disease.

In a fifth aspect, the present invention provides a process forpreparing compounds of Formula I and the N-oxide derivatives, prodrugderivatives, conjugates, protected derivatives, individual isomers andmixture of isomers thereof, and the pharmaceutically acceptable saltsthereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Alkyl” as a group and as a structural element of other groups, forexample halo-substituted-alkyl and alkoxy, can be eitherstraight-chained or branched. C₁₋₆alkoxy includes, methoxy, ethoxy, andthe like. Halo-substituted alkyl includes trifluoromethyl,pentafluoroethyl, and the like.

“Aryl” means a monocyclic or fused bicyclic aromatic ring assemblycontaining six to ten ring carbon atoms. For example, aryl can be phenylor naphthyl, preferably phenyl. “Arylene” means a divalent radicalderived from an aryl group. “Heteroaryl” is as defined for aryl whereone or more of the ring members are a heteroatom. For example heteroarylincludes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl,benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[1,3]dioxole,imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl,isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.“C₆₋₁₀arylC₀₋₄alkyl” means an aryl as described above connected via aalkylene grouping. For example, C₆₋₁₀arylC₀₋₄alkyl includes phenethyl,benzyl, etc.

“Cycloalkyl” means a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing the numberof ring atoms indicated. For example, C₃₋₁₀cycloalkyl includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.“Heterocycloalkyl” means cycloalkyl, as defined in this application,provided that one or more of the ring carbons indicated, are replaced bya moiety selected from —O—, —N═, —NR—, —C(O)—, —S—, —S(O)— or —S(O)₂—,wherein R is hydrogen, C₁₋₄alkyl or a nitrogen protecting group. Forexample, C₃₋₈heterocycloalkyl as used in this application to describecompounds of the invention includes morpholino, pyrrolidinyl,piperazinyl, piperidinyl, piperidinylone,1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, etc.

“Halogen” (or halo) preferably represents chloro or fluoro, but can alsobe bromo or iodo.

The term “modulate” with respect to an LXR receptor refers to regulationof the LXR receptor and its biological activities associated with theLXR pathway (e.g., transcription regulation of a target gene).Modulation of LXR receptor can be up-regulation (i.e., agonizing,activation or stimulation) or down-regulation (i.e. antagonizing,inhibition or suppression). The mode of action of an LXR modulator canbe direct, e.g., through binding to the LXR receptor as a ligand. Themodulation can also be indirect, e.g., through binding to and/ormodifying another molecule which otherwise binds to and activates theLXR receptor, or by stimulating the generation of an endogenous LXRligand. Thus, modulation of LXR includes a change in the bioactivitiesof an LXR agonist ligand (i.e., its activity in binding to and/oractivating an LXR receptor) or a change in the cellular level of theligand.

“Treat”, “treating” and “treatment” refer to a method of alleviating orabating a disease and/or its attendant symptoms.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides compounds, compositions and methods forthe treatment of diseases in which modulation of LXR activity canprevent, inhibit or ameliorate the pathology and/or symptomatology ofthe diseases, which method comprises administering to the animal atherapeutically effective amount of a compound of Formula I.

In one embodiment, compounds of the invention are of Formula Ia:

in which:

-   -   n is selected from 1, 2 and 3;    -   Y is selected from —CH═ and —N═;    -   R₁ is selected from halo, C₁₋₆alkyl, and —C(O)OR₄; wherein R₄ is        selected from hydrogen and C₁₋₆alkyl;    -   R₂ is selected from C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl        and C₃₋₈heterocycloalkyl; wherein any aryl, heteroaryl,        cycloalkyl or heterocycloalkyl of R₂ is optionally substituted        with 1 to 4 radicals independently selected from halo, hydroxy,        C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl and —OC(O)R₅; wherein R₅        is selected from hydrogen and C₁₋₆alkyl; and    -   R₃ is selected from C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl        and C₃₋₈heterocycloalkyl; wherein any aryl, heteroaryl,        cycloalkyl or heterocycloalkyl of R₃ is substituted with 1 to 5        radicals independently selected from halo, hydroxyl, C₁₋₆alkoxy,        halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —OXR₇,        —OXC(O)NR₇R₈, —OXC(O)NR₇XC(O)OR₈, —OXC(O)NR₇XOR₈,        —OXC(O)NR₇XNR₇R₈, —OXC(O)NR₇XS(O)₀₋₂R₈, —OXC(O)NR₇XNR₇C(O)R₈,        —OXC(O)NR₇XC(O)XC(O)OR₈, —OXC(O)NR₇R₉, —OXC(O)OR₇, —OXOR₇,        —OXR₉, —XR₉, —OXC(O)R₉ and —OXC(O)NR₇CR₇[C(O)R₈]₂;        -   wherein            -   X is a selected from a bond and C₁₋₆alkylene;            -   R₇ and R₈ are independently selected from hydrogen,                cyano, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl,                C₂₋₆alkenyl and C₃₋₁₂cycloalkyl-C₀₋₄-alkyl; R₉ is                selected from C₆₋₁₀aryl-C₀₋₄alkyl,                C₅₋₁₀heteroaryl-C₀₋₄-alkyl, C₃₋₁₂cycloalkyl-C₀₋₄alkyl                and C₃₋₈heterocycloalkyl-C₀₋₄-alkyl; wherein any alkyl                of R₉ can have a hydrogen replaced with —C(O)OR₁₀; and                any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of                R₉ is optionally substituted with 1 to 4 radicals                independently selected from halo, C₁₋₆alkyl,                C₃₋₁₂cycloalkyl, halo-substituted-C₁₋₆alkyl, C₁₋₆alkoxy,                halo-substituted-C₁₋₆alkoxy, —XC(O)OR₁₀, —XC(O)R₁₀,                —XC(O)NR₁₀R₁₀, —XS(O)₀₋₂NR₁₀R₁₀ and —XS(O)₀₋₂R₁₀;                wherein R₁₀ is independently selected from hydrogen and                C₁₋₆alkyl.

In another embodiment, R₁ is selected from fluoro, chloro, methyl and—C(O)OCH₃; and R₂ is selected from phenyl, cyclohexyl, cyclopentyl,pyrrolyl, pyrazolyl, naphthyl, benzo[1,3]dioxolyl, thienyl, furanyl andpyridinyl; wherein any aryl, heteroaryl or cycloalkyl of R₂ isoptionally substituted with 1 to 4 radicals independently selected fromfluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, t-butyl, amino,dimethyl-amino, methoxy, trifluoromethyl, trifluoromethoxy and—OC(O)CH₃.

In another embodiment, R₃ is selected from phenyl, benzo[1,3]dioxolyl,pyridinyl, 2,2-difluoro-benzo[1,3]dioxol-5-yl and benzooxazolyl; whereinany aryl or heteroaryl of R₃ is substituted with 1 to 5 radicalsindependently selected from fluoro, chloro, bromo, methoxy, hydroxyl,difluoromethoxy, —OCH₂C(O)NH₂, —OCH₂C(O)OCH₃, —OCH₂C(O)NHCH₃,—OCH₂C(O)N(CH₃)₂, —R₉, —OR₉, —OCH₂R₉, —OCH₂C(O)R₉, —OCH₂C(O)NHR₉,—OCH₂C(O)N(CH₃)R₉, —OCH₂C(O)NHCH₂R₉, —OCH₂CN, —OCH₂C₂H₃, —OCH₂C₂H₄,—O(CH₂)₂OH, —OCH₂C(O)NH(CH₂)₂C(O)OC₂H₅, —OCH₂C(O)NH(CH₂)₂CH₂F,—OCH₂C(O)NHCH₂CH₂F, —OCH₂C(O)NH(CH₂)₂C(O)OH,—OCH₂C(O)NHCH(CH₂R₉)C(O)OC₂H₅, —OCH₂C(O)NHC(O)(CH₂)₂C(O)OCH₃,—OCH₂C(O)NH(CH₂)₂NHC(O)CH₃, —OCH₂C(O)NHCH₂C(O)C₂H₅,—OCH₂C(O)NH(CH₂)₂C(O)OC₄H₉, —OCH₂C(O)NHCH₂C(O)OC₂H₅,—OCH₂C(O)NHCH[C(O)OC₂H₅]₂, —S(O)₂CH₃, —OCH₂C(O)NHCH₂CF₃,—OCH₂C(O)NHCH₂C(O)(CH₂)₂C(O)OCH₃, —OCH₂C(O)N(CH₃)CH₂C(O)OCH₃,—OCH₂C(O)NH(CH₂)₃OC₂H₅, —OCH₂C(O)NH(CH₂)₃OCH(CH₃)₂,—OCH₂C(O)NH(CH₂)₂SCH₃, —OCH₂C(O)NHCH₂CH(CH₃)₂, —OCH₂C(O)NHCH(CH₃)CH₂OH,—OCH₂C(O)NHCH₂CH(CH₃)C₂H₅, —OCH₂C(O)NHCH(CH₃)C(O)OC₂H₅,—OCH₂C(O)NHCH₂CH(CH₃)₂ and —OCH₂C(O)(CH₂)₃OCH(CH₃)₂; wherein R₉ isphenyl, cyclopropyl-methyl, isoxazolyl, benzthiazolyl, furanyl,furanyl-methyl, tetrahydro-furanyl, pyridinyl,4-oxo-4,5-dihydro-thiazol-2-yl, pyrazolyl, isothiazolyl,1,3,4-thiadiazolyl, thiazolyl, phenethyl, morpholino, morpholino-propyl,isoxazolyl-methyl, pyrimidinyl, tetrahydro-pyranyl,2-oxo-2,3-dihydro-pyrimidin-4-yl, piperazinyl, pyrrolyl, piperidinyl,pyrazinyl, imidazolyl, imidazolyl-propyl, benzo[1,3]dioxolyl,benzo[1,3]dioxolyl-propyl, 2-oxo-pyrrolidin-1-yl and2-oxo-pyrrolidin-1-yl-propyl; wherein any alkyl of R₉ can have ahydrogen replaced with —C(O)OC₂H₅; wherein any aryl, heteroaryl orheterocycloalkyl of R₉ is optionally substituted with 1 to 4 radicalsindependently selected from methyl, ethyl, cyclopropyl, methoxy,trifluoromethyl, —OC(O)CH₃, —COOH, —S(O)₂NH₂, —CH(NH₂)═NOH, —C(O)OC₂H₅,—CH₂C(O)OH, —CH₂C(O)OC₂H₅, —CH₂C(O)OCH₃, —C(O)OCH₃, —C(O)NH₂, —C(O)NHCH₃and —C(O)CH₃.

Preferred compounds of Formula I are detailed in the Examples and TableI, infra.

Pharmacology and Utility

Compounds of the invention modulate the activity of LXRs and, as such,are useful for treating diseases or disorders in which LXRs contributeto the pathology and/or symptomatology of the disease. This inventionfurther provides compounds of this invention for use in the preparationof medicaments for the treatment of diseases or disorders in which LXRscontribute to the pathology and/or symptomatology of the disease. LXRmediated diseases or conditions include inflammation, cardiovasculardisease including atherosclerosis, arteriosclerosis, hypercholesteremia,hyperlipidemia and disorders of glucose homeostasis, including insulinresistance, type II diabetes, and obesity.

Lipoprotein metabolism is a dynamic process comprised of the productionof triglyceride and cholesterol rich particles from the liver as verylow-density lipoprotein (VLDL), modification of these lipoproteinparticles within the plasma (VLDL to intermediate density (IDL) tolow-density lipoprotein (LDL)) and clearance of the particles from theplasma, again by the liver. This process provides the transport oftriglycerides and free cholesterol to cells of the body. Reversecholesterol transport is the proposed mechanism by which excesscholesterol is returned to the liver from extra-hepatic tissue.

The process is carried out by high-density lipoprotein (HDL)cholesterol. The combination of lipoprotein production (VLDL, HDL) fromthe liver, modification of particles (all) within the plasma andsubsequent clearance back to the liver, accounts for the steady statecholesterol concentration in plasma. Compounds of this inventionincrease reverse cholesterol transport by increasing cholesterol effluxfrom the arteries. This invention includes the use of compounds of thisinvention for the preparation of a medicament for increasing reversecholesterol transport. Additionally, this invention provides compoundsfor inhibiting cholesterol absorption and the use of compounds of thisinvention for the preparation of a medicament for inhibiting netcholesterol absorption.

The compounds of this invention can also be useful for the prevention ortreatment of inflammation and neurodegenerative diseases or neurologicaldisorders. Accordingly, this invention also provides a method forpreventing or treating inflammation and a method for preventing ortreating neurodegenerative diseases or neurological disorders,particularly neurodegenerative diseases or disorders characterized byneuron degeneration, neuron injury or impaired plasticity orinflammation in the CNS. Particular diseases or conditions that arecharacterized by neuron degeneration, inflammation, cholesterol andlipid abnormalities in the brain and thus benefiting from the growthand/or repair of neurons include stroke, Alzheimer's disease,fronto-temporal dementias (tauopathies), peripheral neuropathy,Parkinson's disease, dementia with Lewy bodies, Huntington's disease,amyotrophic lateral sclerosis and multiple sclerosis and Niemann-Pickdisease. Diseases or conditions that are characterized by neurondegeneration and/or impaired plasticity include psychiatric disorderssuch as schizophrenia and depression. Particular diseases or conditionsthat are characterized by neuronal injury include those conditionsassociated with brain and/or spinal cord injury, including trauma. Inaddition, the compounds of this invention can be used to treat orprevent various diseases with an inflammatory component, such asrheumatoid arthritis, osteoarthritis, psoriasis, asthma, etc.

LXR agonists improve glucose tolerance and enhance glut4 expression(U.S. Provisional Patent Application 60/436,112, filed Dec. 23, 2002;U.S. patent application Ser. No. 10/745,334, filed Dec. 22, 2003). Thereis a coordinated regulation of genes involved in glucose metabolism inliver and adipose tissue. In the liver, LXR agonists inhibit expressionof several genes that are important for hepatic gluconeogenesis, e.g.,PGC-1α, phosphoenolpyruvate carboxykinase (PEPCK), andglucose-6-phosphatase expression. Inhibition of these gluconeogenicgenes is accompanied by an induction in expression of glucokinase, whichpromotes hepatic glucose utilization. It was also found that glut4 mRNAlevels were upregulated by LXR agonists in adipose tissue, and thatglucose uptake in 3T3-L1 adipocytes was enhanced in vitro.

In accordance with these discoveries, the present invention providesmethods for enhancing glut4 expression in cells in a subject byadministering a compound of the invention to the subject. The presentinvention also provides methods for treating diabetes mellitus andrelated disorders, such as obesity or hyperglycemia, by administering toa subject an effective amount of a compound of the invention toameliorate the symptoms of the disease. For example, type II diabetes isamenable to treatment with methods of the present invention. Byenhancing sensitivity to insulin and glucose uptake by cells,administration with a compound of the invention can also treat otherdiseases characterized by insulin dysfunction (e.g., resistance,inactivity or deficiency) and/or insufficient glucose transport intocells.

Compounds of the present invention also regulate expression levels of anumber of genes that play important roles in liver gluconeogenesis.Accordingly, the present invention further provides methods for reducinggluconeogenesis in a subject by modulating expression of such genes(e.g., PGC-1 and PEPCK).

In the pancreas, LXR activation stimulates insulin secretion viamodulation of glucose and lipid metabolism in pancreatic β-cells,suggesting another mechanism for LXR's anti-diabetic effects. LXRmodulators can thus also regulate glucose tolerance by enhancing insulinsecretion from the pancreas.

In accordance with the foregoing, the present invention further providesa method for preventing or treating any of the diseases or disordersdescribed above in a subject in need of such treatment, which methodcomprises administering to said subject a therapeutically effectiveamount (See, “Administration and Pharmaceutical Compositions”, infra) ofa compound of Formula I or a pharmaceutically acceptable salt thereof.For any of the above uses, the required dosage will vary depending onthe mode of administration, the particular condition to be treated andthe effect desired.

Administration and Pharmaceutical Compositions

In general, compounds of the invention will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount can vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Ingeneral, satisfactory results are indicated to be obtained systemicallyat daily dosages of from about 0.03 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, e.g. humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered, e.g.in divided doses up to four times a day or in retard form. Suitable unitdosage forms for oral administration comprise from ca. 1 to 50 mg activeingredient.

Compounds of the invention can be administered as pharmaceuticalcompositions by any conventional route, in particular enterally, e.g.,orally, e.g., in the form of tablets or capsules, or parenterally, e.g.,in the form of injectable solutions or suspensions, topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form or in inhaled forms. Pharmaceutical compositionscomprising a compound of the present invention in free form or in apharmaceutically acceptable salt form in association with at least onepharmaceutically acceptable carrier or diluent can be manufactured in aconventional manner by mixing, granulating or coating methods. Forexample, oral compositions can be tablets or gelatin capsules comprisingthe active ingredient together with a) diluents, e.g., lactose,dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b)lubricants, e.g., silica, talcum, stearic acid, its magnesium or calciumsalt and/or polyethyleneglycol; for tablets also c) binders, e.g.,magnesium aluminum silicate, starch paste, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose and orpolyvinylpyrollidone; if desired d) disintegrants, e.g., starches, agar,alginic acid or its sodium salt, or effervescent mixtures; and/or e)absorbents, colorants, flavors and sweeteners. Injectable compositionscan be aqueous isotonic solutions or suspensions, and suppositories canbe prepared from fatty emulsions or suspensions. The compositions can besterilized and/or contain adjuvants, such as preserving, stabilizing,wetting or emulsifying agents, solution promoters, salts for regulatingthe osmotic pressure and/or buffers. In addition, they can also containother therapeutically valuable substances. Suitable formulations fortransdermal applications include an effective amount of a compound ofthe present invention with a carrier. A carrier can include absorbablepharmacologically acceptable solvents to assist passage through the skinof the host. For example, transdermal devices are in the form of abandage comprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound to the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin. Matrix transdermal formulations can also beused. Suitable formulations for topical application, e.g., to the skinand eyes, are preferably aqueous solutions, ointments, creams or gelswell-known in the art. Such can contain solubilizers, stabilizers,tonicity enhancing agents, buffers and preservatives.

Compounds of the invention can be administered in therapeuticallyeffective amounts in combination with one or more therapeutic agents(pharmaceutical combinations). For example, synergistic effects canoccur with other substances used in the treatment of cardiovascular,inflammatory and/or neurodegenerative diseases. Examples of suchcompounds include fibrates, TZDs, metformin, etc. Where the compounds ofthe invention are administered in conjunction with other therapies,dosages of the co-administered compounds will of course vary dependingon the type of co-drug employed, on the specific drug employed, on thecondition being treated and so forth.

The invention also provides for pharmaceutical combinations, e.g. a kit,comprising a) a first agent which is a compound of the invention asdisclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent. The kit can include instructions forits administration.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the 2compounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of 3 or more activeingredients.

Processes for Making Compounds of the Invention

The present invention also includes processes for the preparation ofcompounds of the invention. In the reactions described, it can benecessary to protect reactive functional groups, for example hydroxy,amino, imino, thio or carboxy groups, where these are desired in thefinal product, to avoid their unwanted participation in the reactions.Conventional protecting groups can be used in accordance with standardpractice, for example, see T. W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Chemistry”, John Wiley and Sons, 1991.

Compounds of Formula I can be prepared by proceeding as in the followingReaction Scheme I:

in which n, Y, Z, R₁, R₂ and R₃ are as defined in the Summary of theInvention. Compounds of Formula I are prepared by reacting a compound offormula 2 with a compound of formula 3 to form a compound of formula 4which is further reacted with a compound of formula 5 or 6. The entirereaction is carried out in the presence of a suitable solvent (e.g.,dichloromethane, or the like) and a suitable base (e.g., DIEA, or thelike). The reaction is carried out in the temperature range of about 5to about 30° C. and takes up to 20 hours to complete.

Additional Processes for Making Compounds of the Invention

A compound of the invention can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase. Alternatively, the salt forms of the compounds of the inventioncan be prepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the invention in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc.,1999.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. While resolution of enantiomers can be carried outusing covalent diastereomeric derivatives of the compounds of theinvention, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chromatography,or preferably, by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. Resolution of the racemic mixture maybe carried out using chiral HPLC. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981.

In summary, the compounds of Formula I can be made by a process, whichinvolves:

(a) that of reaction scheme I; and(b) optionally converting a compound of the invention into apharmaceutically acceptable salt;(c) optionally converting a salt form of a compound of the invention toa non-salt form;(d) optionally converting an unoxidized form of a compound of theinvention into a pharmaceutically acceptable N-oxide;(e) optionally converting an N-oxide form of a compound of the inventionto its unoxidized form;(f) optionally resolving an individual isomer of a compound of theinvention from a mixture of isomers;(g) optionally converting a non-derivatized compound of the inventioninto a pharmaceutically acceptable prodrug derivative; and(h) optionally converting a prodrug derivative of a compound of theinvention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

EXAMPLES

The present invention is further exemplified, but not limited, by thefollowing examples that illustrate the preparation of compounds ofFormula I according to the invention.

Example 15-(4-Chloro-phenyl)-2-(2-difluoromethoxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2-fluoro-phenyl)-methanone

Preparation of 4-chloro-thiobenzoic acid hydrazide

One half of volume of a solution of KOH (1.06 mol) in 400 mL of EtOH issaturated with H₂S. This solution is recombined with the other half ofthe KOH solution and the resulting solution is stirred under N₂ at45-50° C. before adding 4-chlorobenzotrichloride (0.25 mol) at a rate tokeep the temperature at 50-60° C. (˜1.5 hours). The deep red mixture isrefluxed for 30 minutes, then treated with a solution of chloroaceticacid (0.35 mol) and NaHCO₃ (0.35 mol) in H₂O (200 mL). The reactionmixture is reheated under reflux for an additional 5 minutes. Theresulting brownish-red solution is decanted from the sticky resin andacidified with concentrated HCl to pH=1. The red solution oncrystallization yields (4-chloro-thiobenzoylsulfanyl)-acetic acid: ¹HNMR (400 MHz, CDCl₃): δ 7.75 (d, 2H), 7.15 (d, 2H), 4.04 (s, 2H).

To a mixture of (4-chloro-thiobenzoylsulfanyl)-acetic acid (8.31 mmol)in 9 mL of NaOH (1N) is added hydrazine hydrate (36.7 mL). Glacialacetic acid (2.7 mL) is then added to the solution and the mixture isvigorously stirred. The reaction mixture is diluted with CH₂Cl₂ and theorganic layer dried over MgSO₄ to yield 4-chloro-thiobenzoic acidhydrazide: LC/MS (ES⁺) 186.9 (M+1)⁺.

To a heterogeneous mixture of 4-chloro-thiobenzoic acid hydrazide (0.107mmol) in CH₂Cl₂ (1 mL) is added 2-difluoromethoxy-benzaldehyde (0.128mmol) and DIEA (0.128 mmol). After 10 minutes the mixture becomehomogenous and the reaction is complete by TLC and LCMS to give5-(4-chloro-phenyl)-2-(2-difluoromethoxy-phenyl)-2,3-dihydro-[1,3,4]thiadiazolewhich is used in the next step without evaporation of the solvent.

To the solution of5-(4-chloro-phenyl)-2-(2-difluoromethoxy-phenyl)-2,3-dihydro-[1,3,4]thiadiazoleis added DIEA (0.16 mmol) and 2-fluorobenzoyl chloride (0.16 mmol) andthe reaction mixture is stirred for 12 hours at room temperature. Afterevaporation of the solvent, the residue is purified by automatedchromatography (hexane/EtOAc) to give5-(4-chloro-phenyl)-2-(2-difluoromethoxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2-fluoro-phenyl)-methanone:¹H NMR (400 MHz, CDCl₃) δ 7.39-7.35 (m, 1H), 7.34-7.29 (m, 4H), 7.25(dd, J₁=7.8 Hz, J₂=1.2 Hz, 1H), 7.19-7.13 (m, 3H), 7.04 (m, 1H), 6.97(m, 2H), 6.50 (dd, J₁=71.6 Hz, J₂=71.2 Hz, 1H). LC/MS: (ES⁺) 462.8(M+1)⁺.

Example 22-{2-[5-(4-Chloro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-acetamide

To a heterogeneous mixture of 4-chloro-thiobenzoic acid hydrazide (1.3mmol) in 12 mL of CH₂Cl₂ is added 2-(2-formylphenoxy)acetamide (1.53mmol) and DIEA (1.53 mmol). After 10 minutes the mixture becomehomogenous and the reaction is complete by TLC and LCMS to give2-(2-(5-(4-chlorophenyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)phenoxy)-acetamidewhich is used as such in the next step without evaporation of thesolvent.

To the solution of2-(2-(5-(4-chlorophenyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)phenoxy)acetamideis added DIEA (2.0 mmol) and 2,4,6-tri-fluorobenzoyl chloride (2.0 mmol)and the reaction mixture is stirred for 12 hours at room temperature.After evaporation of the solvent, the residue is purified by automatedchromatography (hexane/EtOAc) to give2-{2-[5-(4-chloro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-acetamide:¹H NMR (400 MHz, CDCl₃) δ 7.43 (s, 1H), 7.27 (d, J=8.8, 2H), 7.15 (m,2H), 7.14 (d, J=8.4 Hz, 2H) 6.99 (bs, 1H), 6.84 (t, J=6.4 Hz, 3H), 6.66(d, J=8.4 Hz, 1H), 6.53 (t, J=8.0 Hz, 2H), 5.29 (bs, 1H), 4.47 (d, J=1.6Hz, 2H); LC/MS: (ES⁺) 506.2 (M+1)⁺.

Example 32-{2-[5-(4-Fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-6-methoxy-phenoxy}-acetamide

Preparation of 4-fluorobenzothiohydrazide trifluoroacetic acid salt orhydrochloride salt

To a solution of 4-fluorobenzoic acid (35.7 mmol) in 72 mL of a mixtureof DMF and THF (1:1), is added tert-butyl carbazate (37.5 mmol), EDC(39.3 mmol) and N,N-dimethylaminopyridine (0.54 mmol). After 10 minutesthe mixture becomes homogeneous and stirring is continued for 3 hoursuntil the reaction is complete by TLC and LC/MS. The reaction mixture ispoured into ice. Upon addition of diethylether the organic layer isseparated. The organic layer is washed with sodium bisulfite, saturatedsodium bicarbonate and saturated sodium chloride solution, dried overmagnesium sulfate and concentrated to yieldN′-(4-fluoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester: MS:(ES) 255 (M+1)⁺.

To a mixture of N′-(4-fluoro-benzoyl)-hydrazinecarboxylic acidtert-butyl ester (11.1 mmol) in 10 mL of dry THF is added Lawesson'sreagent (11.6 mmol) and the mixture is heated in the microwave oven at80° C. for 20 minutes The reaction mixture is concentrated and purifiedby automated column chromatography using hexanes/EtOAc: ¹H NMR (400 MHz,CDCl₃) δ 9.8 (bs, 1H), 9.05 (bs, 1H); 8.0-7.97 (m, 2H), 7.31 (t, J=8.4Hz, 2H), 1.73 (s, 9H). LC/MS: (ES) 271 (M+1)⁺.

Trifluoroacetic salt. To a solution ofN′-(4-fluoro-thiobenzoyl)-hydrazinecarboxylic acid tert-butyl ester(1.97 mmol) in CH₂Cl₂ is added trifluoroacetic acid (3 mL) andthioanisole (2.7 mmol). The mixture is stirred at room temperature for 1hour. After evaporation of the solvent the mixture is purified byautomated column chromatography (hexanes/EtOAc) to yield4-fluoro-thiobenzoic acid hydrazide trifluoroacetic acid salt: ¹H NMR(400 MHz, CDCl₃) δ 9.5 (bs, 3H), 7.8-7.76 (m, 2H), 7.05 (t, J=8.4 Hz,2H); LC/MS: (ES) 171 (M+1)⁺.

Hydrochloride salt. To N′-(4-fluoro-thiobenzoyl)-hydrazinecarboxylicacid tert-butyl ester (18.5 mmol) is added HCl (4 N) in 1,4-dioxane (185mmol). The mixture is stirred at room temperature for 1 hour. Hexanes isadded to further precipitate the product. The product is filtered offyielding 4-fluoro-thiobenzoic acid hydrazide hydrochloride salt: ¹H NMR(400 MHz, CH₃OD) δ 7.8-7.75 (m, 2H), 7.09 (t, J=11.6 Hz, 2H). LC/MS:(ES) 171 (M+1)⁺.

Preparation of 3-methoxy-2-triisopropylsilanyloxy-benzaldehyde

O-vanillin (26.3 mmol) is mixed with TIPSCl (39.6 mmol) and imidazole(78.7 mmol) in a microwave vessel. The mixture is heated in themicrowave at 100° C. for 3 minutes. The oily mixture is diluted withEtOAc (100 mL) and washed with NaHSO₄ (1 M) (2×50 mL) and brine (50 mL).After drying with MgSO₄, the filtrate is concentrated. The resultantcrude mixture is purified by silica flash chromatography (2%EtOAc/hexane) to yield 3-methoxy-2-triisopropylsilanyloxy-benzaldehydeas an oil: ¹H NMR (400 MHz, CDCl₃) δ 10.6 (s, 1H), 7.38 (dd, J₁=1.6 Hz,J₂=8 Hz, 1H), 7.04 (dd, J₁=1.6 Hz, J₂=8 Hz, 1H), 6.93 (td, J₁=8 Hz,J₂=0.8 Hz, 1H), 3.82 (s, 3H), 1.34-1.25 (m, 3H), 1.1 (s, 18H); LC/MS(ES⁺): 309 (M+1)⁺.

To a heterogeneous mixture of 4-fluoro-thiobenzoic acid hydrazide salt(2.06 mmol) in 8 mL of CH₂Cl₂ is added3-methoxy-2-triisopropylsilanyloxy-benzaldehyde (2.27 mmol) and DIEA(4.13 mmol). After 15 minutes the mixture becomes homogenous and thereaction is complete by TLC and LCMS to give5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-2,3-dihydro-[1,3,4]thiadiazolewhich is used in the next step without evaporation of the solvent.

To the solution of5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-2,3-dihydro-[1,3,4]thiadiazoleis added DIEA (3.09 mmol) and 2,4,6-tri-fluorobenzoyl chloride (3.09mmol) and the reaction mixture is stirred for 12 hours at roomtemperature. After concentration, the residue is purified by automatedcolumn chromatography (hexane/EtOAc) to yield[5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone.

To[5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone(32.3 mmol) is added tetrabutylammonium fluoride in tetrahydrofuran (1M) (48.5 mmol). The mixture is stirred for an hour and 2-bromo-acetamide(48.5 μmol) is added. The mixture is stirred at room temperature for 12hours. After evaporation of the solvent the residue is purified bypreparative LC/MS (20-100% MeCN/H₂O) to give2-{2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-6-methoxy-phenoxy}-acetamide:¹H NMR (400 MHz, CDCl₃): δ 7.63-7.62 (m, 2H), 7.57 (s, 1H), 7.22-7.12(m, 3H), 7.02 (dd, J₁=8.4 Hz, J₂=2 Hz, 2H), 6.9 (bs, 1H), 6.85 (t, J=8.4Hz, 2H), 6.10 (s, 1H), 4.83 (d, J=15.2 Hz, 1H), 4.68 (d, J=15.2 Hz, 1H),3.94 (s, 3H).

Example 43-{3-[5-(4-Fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxymethyl}-benzoicacid methyl ester

Preparation of 2-Methoxy-3-triisopropylsilanyloxy-benzaldehyde

Guaiacol (2-methoxy-phenol, 34.6 mmol) is mixed with TIPSCl (51.9 mmol)and imidazole (103.8 mmol) in a tube. The mixture is heated in themicrowave oven at 180° C. for 3 minutes. The oily mixture is dilutedwith EtOAc (100 mL) and washed with NaHSO₄ (1 M) (2×50 mL) and brine (50mL). After drying over anhydrous Na₂SO₄, the filtrate is concentrated.The resultant crude mixture is purified by silica flash chromatography(2% EtOAc/hexane) to yield triisopropyl-(2-methoxy-phenoxy)-silane as acolorless oil. Yield: 69%. ¹H NMR (400 MHz, CDCl₃) δ 6.8-6.89 (m, 4H),3.8 (s, 3H), 1.22-1.28 (m, 3H), 1.1 (s, 9H), 1.08 (s, 9H). LC/MS (ES⁺):(M+1), 281.2. R_(f)=0.8 (5% EtOAc/hexane). (Note: Alternatively,conventional heating might be adopted in which case NMP is the solventof choice).

nBuLi (2.5 M in hexanes) (36 mmol) is mixed with TMEDA (36 mmol) at 0°C. in a dry round bottom flask for 10 minutes. A solution oftriisopropyl-(2-methoxy-phenoxy)-silane (24 mmol) in 25 mL of dry THF isadded to the above mixture. The mixture is warmed up to room temperaturein 2 hours by removal of the ice bath. The slightly yellow solution isthen transferred to another dry flask containing dry 7.5 mL of DMF atroom temperature. The mixture is stirred overnight. HCl (1 M) is addedto the mixture to quench the reaction. The mixture is diluted with EtOAc(100 mL), washed with HCl (1 M) (2×100 mL) and brine (50 mL) and finallydried over anhydrous Na₂SO₄. Purification is accomplished by silicaflash chromatography (5% EtOAc/hexane) to yield3-methoxy-2-triisopropylsilanyloxy-benzaldehyde as a colorless oil whichneeds to be stored at low temperatures: ¹H NMR (400 MHz, CDCl₃) δ 10.4(s, 1H), 7.42 (dd, J₁=7.7 Hz, J₂=1.7 Hz, 1H), 7.67 (d, J₁=8 Hz, J₂=1.7Hz, 1H), 7.04 (t, J=8.4 Hz, 1H), 3.96 (s, 3H), 1.26-1.35 (m, 3H), 1.13(s, 9H), 1.12 (s, 9H). LC/MS (ES⁺): (M+1) 309.2. R_(f)=0.4 (5%EtOAc/hexane).

N′-(4-fluoro-thiobenzoyl)-hydrazinecarboxylic acid tert-butyl ester(1.23 mmol) is dissolved in 5 mL of CH₂Cl₂ at room temperature in a dryround bottom flask. Removal of the ester group is accomplished addingTFA (2 mL) to the solution at room temperature. The reaction is completeafter 30 minutes as determined by LC/MS. Solvent is removed in vacuo.The resultant oil is dried on the vacuum line for 30 minutes anddissolved in 1 mL of dry CH₂Cl₂. This solution is added to a mixture of3-methoxy-2-triisopropylsilanyloxy-benzaldehyde (1.23 mmol) and DIEA(4.9 mmol) in 1 mL of dry CH₂Cl₂. The mixture is allowed to stand atroom temperature in the presence of molecular sieves for 5 minutes.2,4,6-Trifluorobenzoyl chloride (1.6 mmol) is added and the reactionmixture is kept at room temperature for 16 hours. HCl (1 M) (10 mL) isadded to the mixture to quench the reaction. The mixture is diluted withEtOAc (50 mL), washed with HCl (1 M) (2×10 mL) and brine (50 mL) anddried over anhydrous Na₂SO₄. Purification is accomplished by silicaflash chromatography (5% EtOAc/hexane) to give[5-(4-fluoro-phenyl)-2-(2-methoxy-3-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanoneas a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.54 (dd, J₁=8.8 Hz,J₂=5.3 Hz, 2H), 7.51 (s, 1H), 7.04 (t, J=8.6 Hz, 2H), 6.95 (t, J=7.8 Hz,1H), 6.87 (t, J=8.8 Hz, 2H), 6.77 (t, J=7.9 Hz, 2H), 4.03 (s, 3H),1.27-1.36 (m, 3H), 1.14 (dd, J₁=J₂=6.3 Hz, 18H); LC/MS (ES⁺): (M+1)309.2. R_(f)=0.4 (5% EtOAc/hexanes).

[5-(4-fluoro-phenyl)-2-(2-methoxy-3-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone(0.02 mmol) is treated with tetrabutylammonium fluoride (1 M in THF)(0.04 mmol) at room temperature for 30 minutes. 3-Bromomethyl-benzoicacid methyl ester (0.04 mmol) is then added. After 30 minutes, thereaction is complete as determined by LC/MS. The mixture is diluted withacetonitrile and purified by preparative LC/MS (20-100% MeCN/H₂O) togive3-{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxymethyl}-benzoicacid methyl ester as white solid after evaporation of solvent: ¹H NMR(400 MHz, CDCl₃) δ 8.14 (s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.7Hz, 1H), 7.47-7.55 (m, 4H), 7.01-7.07 (m, 3H), 6.94 (t, J=8.3 Hz, 2H),6.77 (t, J=8.5 Hz, 2H), 5.16 (s, 2H), 4.07 (s, 3H), 3.94 (s, 3H). LC/MS(ES⁺): (M+1) 610.9.

Example 54-{3-[5-(4-Fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxymethyl}-benzoicacid

[5-(4-fluoro-phenyl)-2-(2-methoxy-3-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone(0.02 mmol) is treated with tetrabutylammonium fluoride (1.0 M in THF)(0.04 mmol) at room temperature for 30 minutes. The reaction is completeby LC/MS analysis. 4-Bromomethyl-benzoic acid methyl ester (0.04 mmol)is added. After 30 minutes, the reaction is complete as determined byLC/MS. After dilution with MeOH (0.5 mL), LiOH (1 M) (0.5 mL) is added.After stirring for 1 hour, the solvent is removed from the reactionmixture. A mixture of MeOH/DMSO is added to the residue and resultantsolution is filtered. The clear solution is purified by preparativeLC/MS (20-100% MeCN/H₂O) to give4-{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxymethyl}-benzoicacid as white solid after removal of solvent: ¹H NMR (400 MHz, CDCl₃) δ8.14 (d, J=8 Hz, 2H), 7.53-7.58 (m, 5H), 7.03-7.05 (m, 3H), 6.94-6.95(m, 2H), 6.77 (t, J=8.2 Hz, 2H), 5.2 (s, 2H), 4.08 (s, 3H); LC/MS (ES⁺):(M+1) 597.3.

Example 62-{2-[5-(4-Chloro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-N-methyl-acetamide

(2-Formyl-phenoxy)-acetic acid (0.5 mmol) is dissolved in 1 mL ofCH₂Cl₂. Oxalyl chloride (0.066 mL) is added along with one drop of DMF.After 1 hour, the solvent is removed from the mixture. The resultantresidue is dissolved in 1 mL of CH₂Cl₂ and added to 1 mL of NH₂Me in THF(2 M) at ambient temperature. After 16 hours of stiffing, the solvent isremoved and the mixture is purified by preparative TLC (10% MeOH/EtOAc)to yield the product 2-(2-formyl-phenoxy)-N-methyl-acetamide as an offwhite solid: LC/MS (ES⁺): 194.1 (M+1)⁺.

The 2-(2-formyl-phenoxy)-N-methyl-acetamide (0.0311 mmol) is added to4-chloro-thiobenzoic acid hydrazide (0.0342 mmol) in 0.1 mL of CH₂Cl₂.After 10 minutes, DIEA (0.05 mL) and 2,4,6-trifluoro-benzoyl chloride(0.0467 mmol) are added. The mixture is kept at room temperatureovernight. After removal of solvent, the residue is purified bypreparative HPLC (20-100% MeCN/H₂O gradient) to give the product2-{2-[5-(4-chloro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-N-methyl-acetamideas an off white solid: LC/MS (ES⁺): 520.1 (M+1)⁺.

Example 7N-Cyclopropylmethyl-2-{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-acetamide

[5-(4-fluoro-phenyl)-2-(2-methoxy-3-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone(3.31 mmol), prepared as described in example 4, is treated withtetrabutylammonium fluoride (1 M in THF) (4.97 mmol) at room temperaturefor 40 minutes. Methyl bromoacetate (4.97 mmol) is then added. After 12hours, the reaction is complete as determined by LC/MS. Purification isaccomplished by silica flash chromatography (25% EtOAc/hexane) to give{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-aceticacid methyl ester: ¹H NMR (400 MHz, CDCl₃) δ 7.52 (m, 3H), 7.04 (m, 3H),6.95 (dd, J₁=8.4 Hz, J₂=1.6 Hz, 1H), 6.82 (dd, J₁=8 Hz, J₂=1.6 Hz), 6.76(m, 2H), 4.7 (s, 2H), 4.1 (s, 3H); LC/MS (ES⁺): 505.1 (M+1)⁺.

To a solution of{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-aceticacid methyl ester (2.47 mmol) in 30 mL of a mixture of THF and MeOH(3:2), is added LiOH (1 M) (25 mL). After stiffing for 12 hours thereaction is complete as determined by LC/MS. The reaction is dilutedwith ethyl acetate and water, washed with brine and dried over MgSO₄ andthe solvent is removed from the reaction mixture to yield{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-aceticacid: LC/MS (ES⁺): 521.1 (M+1)⁺.

To a solution of{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-aceticacid (0.029 mmol) in 1 mL of DMF is added DIEA (0.058 mmol), HATU (0.058mmol) and cyclopropyl methylamine (0.058 mmol). The reaction mixture isstirred for 12 hours. The mixture is purified by preparative LC/MS(20-100% MeCN/H₂O) to giveN-cyclopropylmethyl-2-{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-acetamide:¹H NMR (400 MHz, CDCl₃) δ 7.55-7.51 (m, 3H), 7.12-6.99 (m, 4H), 6.9 (d,J=7.6 Hz, 2H), 6.77 (t, J=8.4 Hz, 2H), 4.56 (s, 2H), 4.08 (s, 3H),3.26-3.2 (m, 2H), 1.02-0.99 (m, 1H), 0.57-0.52 (m, 2H), 0.25 (m, 2H);LC/MS (ES⁺): 574.1 (M+1)⁺.

Example 82-{2-[5-(4-Fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-N-(5-methyl-isoxazol-3-yl)-acetamide

[5-(4-Fluoro-phenyl)-2-(2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone(3.4 mmol), prepared in a similar manner as described for[5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanonein example 3, is treated with tetrabutylammonium fluoride (1.0 M in THF)(5.1 mmol) at room temperature for 40 minutes. Methyl bromoacetate (5.1mmol) is then added. After 12 hours, the reaction is complete asdetermined by LC/MS. Purification is accomplished by silica flashchromatography (25% EtOAc/hexane) to give{2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-aceticacid methyl ester: ¹H NMR (400 MHz, CDCl₃) δ 7.61 (s, 1H), 7.54 (m, 2H),7.04 (m, 3H), 7.01 (d, J=8.4 Hz, 1H) 6.95 (bs, 2H), 4.94 (s, 2H), 4.01(s, 3H). MS: (ES⁺) 535.1 (M+1); LC/MS (ES⁺): 535.1 (M+1)⁺.

To a solution of{2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-aceticacid methyl ester (2.93 mmol) in 30 mL of a mixture of THF and MeOH(3:2), is added LiOH (1 M) (30 mL). After stirring for 12 hours thereaction is complete as determined by LC/MS. The reaction is dilutedwith ethyl acetate and water, washed with brine and dried over MgSO₄ andthe solvent is removed from the reaction mixture to yield{2-[5-(4-Fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-aceticacid: ¹H NMR (400 MHz, acetone-d₆) δ 7.66 (m, 3H), 7.39 (m, 1H), 7.3(dd, J₁=7.6 Hz, J₂=1.6 Hz, 1H), 7.22 (m, 4H), 7.13 (m, 1H), 7.07 (t,J=7.6 Hz, 1H), 4.94 (s, 2H); LC/MS (ES⁺): 491.0 (M+1)⁺.

To a solution of{2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-aceticacid (0.031 mmol) in DMF (1 mL) is added DIEA (0.058 mmol), HATU (0.058mmol) and 5-methyl-isoxazol-3-ylamine (0.058 mmol). The reaction mixtureis stirred for 12 hours. The mixture is purified by preparative LC/MS(20-100% MeCN/H₂O) to give2-{2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-N-(5-methyl-isoxazol-3-yl)-acetamide:¹H NMR (400 MHz, CDCl₃) δ 7.55-7.51 (m, 3H), 7.35-7.26 (m, 2H),7.05-6.96 (m, 3H), 6.85 (d, J=8 Hz, 1H), 6.69 (t, J=7.6 Hz, 2H), 6.56(s, 1H), 4.72 (s, 2H), 2.33 (s, 3H); LC/MS (ES⁺): 571.1 (M+1)⁺.

Example 93-{2-[5-(4-Fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-benzamide

[5-(4-Fluoro-phenyl)-2-(2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone(41 mmol), prepared in a similar manner as described for[5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanonein example 3, is treated with tetrabutylammonium fluoride (1.0 M in THF)(48 mmol) at room temperature for 40 minutes. The solvent is removed invacuo and dried over MgSO₄ to yield[5-(4-fluoro-phenyl)-2-(2-hydroxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanoneto be used without further purification.

To[5-(4-fluoro-phenyl)-2-(2-hydroxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone(41 mmol) dissolved in acetonitrile (1 mL) is added K₂CO₃ (61.5 mmol)and 3-bromomethyl-benzamide (94.2 mmol) and the mixture is heated at 90°C. After 12 hours, the reaction is complete as determined by LC/MS.Purification is accomplished by preparative LC/MS (20-100% MeCN/H₂O) togive3-{2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-benzamide:¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.9 (d, J=7.6 Hz, 1H), 7.7 (s,1H), 7.6-7.5 (m, 4H) 7.35 (d, J=7.6 Hz, 1H), 7.06 (t, J=8.4 Hz, 1H),6.99 (t, J=7.6 Hz, 2H), 6.88 (d, J=8 Hz), 6.79 (t, J=8.4 Hz, 2H), 6.26(bs, 1H), 5.33 (d, J=7.6 Hz); LC/MS (ES⁺): 566.1 (M+1)⁺.

Example 102-{2-[5(4-Fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-furan-3-carboxylicacid

[5-(4-Fluoro-phenyl)-2-(2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone(0.67 mmol), prepared as described for[5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanonein example 3, is treated with tetrabutylammonium fluoride (1.0 M in THF)(1.3 mmol) at room temperature. After 15 minutes, methyl2-(bromomethyl)-3-furoate (0.74 mmol) is added and the mixture isstirred for an additional 12 hours. The solvent is removed in vacuo andthe residue is purified on silica to yield2-{2-[5(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-furan-3-carboxylicacid methyl ester as a yellow solid: LC/MS (ES⁺): 571.1 (M+1)⁺.

To a solution of2-{2-[5(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-furan-3-carboxylicacid methyl ester (0.49 mmol) in THF/MeOH/H₂O (3:2:1), is added LiOH (3N) (4.9 mmol). After stirring for 12 hours, the reaction is acidifiedwith HCl (1 N) and extracted with ethyl acetate. The organic layer isdried over MgSO₄, filtered, and concentrated. The residue is purifiedusing preparative LC/MS to give2-{2-[5(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-furan-3-carboxylicacid as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.23 (m, 3H), 7.20(d, J=1.9, 1H), 7.10-7.05 (m, 1H), 7.03-6.99 (m, 1H), 6.86 (d, J=8.1,1H), 6.78-6.74 (m, 3H), 6.55 (d, J=1.9, 1H), 6.55-6.50 (m, 2H),5.38-5.21 (m, 2H); LC/MS (ES⁺): 557.1 (M+1)⁺.

Example 11[2-(2-Difluoromethoxy-phenyl)-5-(6-methyl-pyridin-3-yl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone

N′-(6-Methyl-pyridine-3-carbothioyl)-hydrazinecarboxylic acid tert-butylester (0.1 mmol) prepared as described in example 3 forN′-(4-fluoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester, istreated with TFA (1 mmol) in dry CH₂Cl₂ (1 mL) at room temperature for30 minutes. Solvent is removed and the residue is dissolved in dryCH₂Cl₂ (1 mL). DIEA (0.287 mmol) is added to the solution and themixture is treated with 2-difluoromethoxy-benzaldehyde (0.12 mmol) inthe presence of 4 Å molecular sieves. 2,4,6-Trifluorobenzoyl chloride(0.15 mmol) is added after 5 minutes. The mixture is kept at ambienttemperature for 16 hours and purified by preparative HPLC (20-100%MeCN/H₂O) to yield[2-(2-difluoromethoxy-phenyl)-5-(6-methyl-pyridin-3-yl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone:¹H NMR (400 MHz, CDCl₃) 8.71 (d, J=2.1 Hz, 1H), 7.81 (dd, J₁=8.2 Hz,J₂=2.2 Hz, 1H), 7.53 (s, 1H), 7.36-7.4 (m, 2H), 7.26 (d, J=8.1 Hz, 2H),7.18 (d, J=8.3 Hz, 1H), 6.78 (t, J=8.3 Hz, 2H), 6.67 (dd, J₁=75.0 Hz,J₂=71.7 Hz, 1H), 2.64 (s, 3H); LC/MS (ES⁺): (M+1) 480.1.

Example 12[2-(2-Difluoromethoxy-phenyl)-5-(6-methyl-pyridin-3-yl)-[1,3,4]thiadiazol-3-yl]-(2-hydroxy-phenyl)-methanone

(2-(2-(Difluoromethoxy)phenyl)-5-(6-methylpyridin-3-yl)-1,3,4-thiadiazol-3(2H)-yl)(2-acetoxyphenyl)methanone(0.02 mmol) prepared in a similar manner as described in experiment 11for[2-(2-difluoromethoxy-phenyl)-5-(6-methyl-pyridin-3-yl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone,is dissolved in THF/MeOH (1 mL/0.5 mL) and treated with aqueous LiOH (1M) (0.5 mL) at room temperature for 30 minutes. Aqueous HCl (3 M) isadded to adjust the pH to 5-6. Solvent is removed and the residue ispurified by preparative HPLC (20-100% MeCN/H₂O) to yield[2-(2-difluoromethoxy-phenyl)-5-(6-methyl-pyridin-3-yl)-[1,3,4]thiadiazol-3-yl]-(2-hydroxy-phenyl)-methanone:¹H NMR (400 MHz, CDCl₃) 9.02 (d, J=2.0 Hz, 1H), 8.41 (d, J=8.6 Hz, 1H),8.23 (dd, J₁=8.2 Hz, J₂=2.2 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.65 (s,1H), 7.62 (dd, J₁=7.8 Hz, J₂=1.3 Hz, 1H), 7.45-7.53 (m, 5H), 6.97-7.01(m, 2H), 2.79 (s, 3H); LC/MS (ES⁺): (M+1) 442.1.

Example 13[2-(2-Difluoromethoxy-phenyl)-5-(6-fluoro-pyridin-3-yl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone

N′-(6-fluoro-pyridine-3-carbothioyl)-hydrazinecarboxylic acid tert-butylester (0.044 mmol) prepared as described in example 3 forN′-(4-fluoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester, istreated with TFA (0.44 mmol) and thioanisole (0.44 mmol) in dry CH₂Cl₂(1 mL) at room temperature for 30 minutes. The solvent is removed andthe residue is dissolved in dry CH₂Cl₂ (1 mL). DIEA (0.22 mmol) is addedto the solution and the mixture is treated with2-difluoromethoxy-benzaldehyde (0.067 mmol) in the presence of 4 Åmolecular sieves. 2,4,6-Trifluorobenzoyl chloride (0.089 mmol) is addedafter 5 minutes. The mixture is kept at room temperature for 16 hoursand purified by preparative silica gel TLC (30% EtOAc/hexane) to yield[2-(2-difluoromethoxy-phenyl)-5-(6-fluoro-pyridin-3-yl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone:¹H NMR (400 MHz, CDCl₃) 8.39 (s, 1H), 7.93-7.97 (m, 1H), 7.54 (s, 1H),7.37-7.41 (m, 2H), 7.24-7.27 (m, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.97 (dd,J₁=8.6 Hz, J₂=2.7 Hz, 1H), 6.78 (t, J=8.3 Hz, 2H), 6.67 (dd, J₁=75.0 Hz,J₂=71.7 Hz, 1H); LC/MS (ES⁺): (M+1) 484.1.

Example 143-{4-[5-(3,4-Difluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-benzooxazol-2-yl}-benzoicacid

2-Amino-3-methyl-phenol (6.09 mmol) is heated with 3-formyl-benzoic acidmethyl ester (6.09 mmol) in MeOH (6 mL) at 60° C. for 30 minutes. Thesolvent is removed from the mixture to obtain a dark red oil which isdissolved in dry CH₂Cl₂ (6 mL) at room temperature and treated with DDQ(6.4 mmol) for 16 hours. The mixture is diluted with EtOAc and pouredonto saturated aqueous NaHCO₃. The aqueous phase is further extractedwith EtOAc and the combined organic phases are dried over Na₂SO₄.Filtration and removal of the solvent yields a residue which is purifiedby silica gel chromatography (5-10% EtOAc/hexane) to yield3-(4-methyl-benzooxazol-2-yl)-benzoic acid methyl ester as a whitesolid: ¹H NMR (400 MHz, CDCl₃) 8.92 (d, J=1.6 Hz, 1H), 8.47 (dt, J₁=7.8Hz, J₂=1.5 Hz, 1H), 8.2 (dt, J₁=7.8 Hz, J₂=1.4 Hz, 1H), 7.61 (t, J=7.9Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.17 (t, J=7.5Hz, 1H), 3.99 (s, 3H), 2.69 (s, 3H); LC/MS (ES⁺): (M+1) 268.1.

A solution of 3-(4-methyl-benzooxazol-2-yl)-benzoic acid methyl ester(1.2 mmol), N-bromo succinimide (1.5 mmol) and AIBN (0.3 mmol) in CCl₄are heated in microwave at 100° C. for 30 minutes (1 mL). The mixture isfiltered and concentrated to yield the crude3-(4-bromomethyl-benzooxazol-2-yl)-benzoic acid methyl ester. LC/MS(ES⁺): (M⁺) 346.1, 348.1, (M-Br) 266.1, 268.1.

The crude 3-(4-bromomethyl-benzooxazol-2-yl)-benzoic acid methyl esteris treated with HMTA (1.8 mmol) in acetic acid/H₂O (3 mL/1.5 mL) in amicrowave oven at 130° C. for 20 minutes. The solvent is removed and themixture is purified by silica gel chromatography (10-20% EtOAc/hexane)to yield 3-(4-formyl-benzooxazol-2-yl)-benzoic acid methyl ester as awhite solid. Yield: 32%. ¹H NMR (400 MHz, CDCl₃) 10.8 (s, 1H), 8.97 (s,1H), 8.53 (d, J=7.8 Hz, 1H), 8.26 (d, J=7.8 Hz, 1H), 7.94 (dd, J₁=7.7Hz, J₂=1 Hz, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.51(t, J=7.9 Hz, 1H), 4.0 (s, 3H). LC/MS (ES⁺): (M+1) 282.1, (M+Na) 304.1.

N′-(3,4-Difluoro-thiobenzoyl)-hydrazinecarboxylic acid tert-butyl ester(0.1 mmol) prepared as described in example 3 forN′-(4-fluoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester, istreated with TFA (1 mmol) in dry CH₂Cl₂ (1 mL) at room temperature for30 minutes. Solvent is removed and the residue is dissolved in dryCH₂Cl₂ (1 mL). DIEA (0.57 mmol) is added to the solution and the mixtureis treated with 3-(4-formyl-benzooxazol-2-yl)-benzoic acid methyl ester(0.064 mmol) in the presence of 4 Å molecular sieves.2,4,6-Trifluorobenzoyl chloride (0.15 mmol) is added after 5 minutes.The mixture is kept at room temperature for 16 hours and purified bypreparative HPLC (20-100% MeCN/H₂O) to yield3-{4-[5-(3,4-difluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-benzooxazol-2-yl}-benzoic acid methyl ester. LC/MS (ES⁺): (M+1) 610.0, (M+Na)632.0.

3-{4-[5-(3,4-Difluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-benzooxazol-2-yl}-benzoicacid methyl ester (0.02 mmol) is dissolved in THF/MeOH (1 mL/0.5 mL) andtreated with aqueous LiOH (1 M) (0.5 mL) at room temperature for 30minutes. Aqueous HCl (3 M) is added to adjust the pH to 5-6. The solventis removed and the residue is purified by preparative HPLC (20-100%MeCN/H₂O) to yield3-{4-[5-(3,4-difluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-benzooxazol-2-yl}-benzoicacid: ¹H NMR (400 MHz, CDCl₃) 8.95 (s, 1H), 8.48 (d, J=7.9 Hz, 1H), 8.27(d, J=7.8 Hz, 1H), 7.92 (s, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.6 (dd, J₁=7.7Hz, J₂=1.2 Hz, 1H), 7.46 (m, 1H), 7.29-7.42 (m, 3H), 7.19 (q, J=8.2 Hz,1H), 6.76-6.81 (m, 2H); LC/MS (ES⁺): (M+1) 596.0, (M+Na) 618.0.

Example 154-{3-[5-4-Fluoro-phenyl)-3-(2-hydroxy-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxymethyl}-benzenesulfonamide

4-(3-Formyl-2-methoxy-phenoxymethyl)-N,N-bis-(4-methoxy-benzyl)-benzenesulfonamide

A solution of 4-(bromomethyl)benzenesulfonyl chloride (5.6 mmol) in 5 mLof CH₂Cl₂ at 25° C. is treated with Et₃N (8.4 mmol) followed bybis-(4-methoxy-benzyl)-amine (5.8 mmol). The reaction is stirred for 12hours, diluted with H₂O, extracted with CH₂Cl₂, dried (MgSO₄), filteredand concentrated. The resultant crude material is purified by silicaflash chromatography (20% EtOAc/hexanes) to yield4-bromomethyl-N,N-bis-(4-methoxy-benzyl)-benzenesulfonamide: ¹H NMR (400MHz, CDCl₃): δ 7.72 (apparent t, J=8.4 Hz, 2H), 7.44 (dd, J₁=1.6 Hz,J₂=8.4 Hz, 2H), 6.91-6.86 (m, 4H), 6.69 (d, J=8.8 Hz, 4H), 4.5 (s, 2H),4.19 (s, 4H), 3.71 (s, 3H); LC/MS: (ES⁺) 490.1 (M+1)⁺.

2-Methoxy-3-triisopropylsilanyloxy-benzaldehyde (2.9 mmol), prepared asdescribed in example 4, and4-bromomethyl-N,N-bis-(4-methoxy-benzyl)-benzenesulfonamide (3.0 mmol)in anhydrous THF (4 mL) are treated with 4.4 mL of a 1.0 M solution ofTBAF in THF. The reaction is stirred for 12 hours at ambient temperatureand concentrated. The resultant material was purified by silica flashchromatography (30% EtOAc/hexanes) to yield4-(3-formyl-2-methoxy-phenoxymethyl)-N,N-bis(4-methoxy-benzyl)-benzamide:¹H NMR (400 MHz, CDCl₃): δ 10.45 (s, 1H), 7.85 (d, J=8 Hz, 2H), 7.58 (d,J=8 Hz, 2H), 7.48 (dd, J₁=1.2 Hz, J₂=7.6 Hz, 1H), 7.11-7.19 (m, 2H),6.97 (d, J=8.8 Hz, 4H), 6.74 (d, T=8.4 Hz, 4H), 5.23 (s, 2H), 4.26 (s,4H), 4.05 (s, 3H), 3.77 (s, 6H); LC/MS: (ES⁺) 562.6 (M+1)⁺.

4-Fluorobenzothiohydrazide hydrochloride salt (0.045 mmol) as preparedin example 3 is dissolved in CH₂Cl₂ (1 mL). DIEA (0.133 mmol) is addedto the solution and the mixture is treated with4-(3-formyl-2-methoxy-phenoxymethyl)-N,N-bis(4-methoxy-benzyl)-benzamide(0.047 mmol) in the presence of 4 Å molecular sieves. Acetic acid2-chlorocarbonyl-phenyl ester (0.047 mmol) is added after 5 minutes. Themixture was kept at ambient temperature for 16 hours and concentrated.The resultant material is dissolved in trifluoroacetic acid. After 3hours, the reaction mixture is concentrated. The crude material isdissolved in DMSO and purified by preparative LC/MS (20-100% MeCN/H₂O)to give4-{3-[5-4-fluoro-phenyl)-3-(2-hydroxy-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxymethyl}-benzenesulfonamideas a white solid after evaporation of solvent: ¹H NMR (400 MHz, CDCl₃):δ 11.27 (s, 1H), 8.55 (dd, J₁=1.2 Hz, J₂=8 Hz, 1H), 7.96 (d, J=8 Hz,2H), 7.71-7.77 (m, 2H), 7.59-7.64 (m, 3H), 7.42-7.47 (m, 1H), 7.12-7.8(m, 2H), 6.95-7.03 (m, 3H), 6.86-6.92 (m, 2H), 5.2 (s, 2H), 4.77 (s,2H), 4.07 (s, 3H); LC/MS: (ES⁺) 594.0 (M+1)⁺.

Example 163-{3-[5-(4-Fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxymethyl}-N-hydroxy-benzamidine

To3-{2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-benzamide(0.1 mmol) is charged 1 mL of SOCl₂. The mixture is heated at 100° C. inthe microwave oven for 25 minutes. Solvent is removed. The residue isdissolved in EtOH (1 mL). NH₂OH (50% aqueous solution, 0.06 mL) ischarged. The mixture is heated at 100° C. in microwave for 25 minutes.Purification by preparative LC/MS (20-100% MeCN/H₂O) to give3-{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxymethyl}-N-hydroxy-benzamidine.¹H NMR (400 MHz, CDCl₃) δ 7.7 (d, J=7 Hz, 1H), 7.64 (s, 1H), 7.52-7.61(m, 4H), 7.5 (s, 1H), 7.03-7.08 (m, 2H), 7.0 (d, J=8.2 Hz, 1H), 6.95 (d,J=7.9 Hz, 1H), 6.9 (d, J=6.8 Hz, 1H), 6.76 (t, J=8 Hz, 2H), 6.41 (bs,2NH), 5.21 (dd, J=14.5, 12.8 Hz, 2H), 4.04 (s, 3H); LC/MS (ES⁺): 611.1(M+1)⁺.

Example 172-{3-[5-(4-Fluoro-phenyl)-3-(2-hydroxy-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-N-(2-hydroxy-1-methyl-ethyl)-acetamide

To{3-[5-(4-Fluoro-phenyl)-3-(2-hydroxy-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-aceticacid (0.27 mmol) in dry DMF (0.5 mL) is added HATU (1.35 mmol), DIEA(0.45 mL, 2.7 mmol) and 2-amino-propan-1-ol. The mixture is kept atambient temperature for 16 hours. The residue is diluted with EtOH (1mL). Purification of the mixture by preparative LC/MS (30-100% MeCN/H₂O)gives2-{3-[5-(4-fluoro-phenyl)-3-(2-hydroxy-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-N-(2-hydroxy-1-methyl-ethyl)-acetamide.¹H NMR (400 MHz, CDCl₃) δ 11.2 (s, 1H), 8.53 (m, 1H), 7.73 (m, 2H), 7.6(s, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.15 (t, J=8 Hz, 2H), 6.9-7.1 (m, 5H),4.58 (s, 2H), 4.14 (m, 1H), 4.06 (s, 3H), 3.69 (m, 1H), 3.59 (m, 1H),2.1 (bs, 2H), 1.23 (m, 3H); LC/MS (ES⁺): 540.1 (M+1)⁺.

Example 186-{2-Cyanomethoxy-3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-pyridine-2-carboxylicacid ethyl ester

To 2,3-dihydroxybenaldehyde (1 mmol) in dry DMSO (2.5 mL) is added NaH(60% suspension in oil, 2.5 mmol). After 10 minutes,6-bromomethyl-pyridine-2-carboxylic acid ethyl ester (1 mmol) is added.After 1 hour, bromoacetonitrile (0.07 mL, 1 mmol) is introduced atambient temperature and mixture is stirred for 16 hours. Saturatedaqueous NH₄Cl solution is used to quench the reaction and the mixture isextracted with EtOAc. After drying over sodium sulfate, solvent isremoved. Purification of the mixture by preparative HPLC (20-70%MeCN/H₂O) gives6-(2-cyanomethoxy-3-formyl-phenoxymethyl)-pyridine-2-carboxylic acidethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 10.4 (s, 1H), 8.1 (d, J=7.7 Hz,1H), 7.9 (t, J=7.9 Hz, 1H), 7.7 (d, J=8.2 Hz, 1H), 7.5 (dd, J=8.2, 2.4Hz, 1H), 7.24 (m, 2H), 5.42 (s, 2H), 5.14 (s, 2H), 4.5 (q, J=7.2 Hz,2H), 1.45 (t, J=7 Hz, 3H); LC/MS (ES⁺): 341.2 (M+1)⁺.

6-{2-Cyanomethoxy-3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-pyridine-2-carboxylicacid ethyl ester is prepared in a similar manner as described for[5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanonein example 3 using6-(2-cyanomethoxy-3-formyl-phenoxymethyl)-pyridine-2-carboxylic acidethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 8.1 (d, J=7.9 Hz, 1H), 7.94 (t,J=7.9 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.54-7.58 (m, 3H), 7.05-7.14 (m,3H), 7.01 (d, J=7.3 Hz, 1H), 6.96 (d, J=8.9 Hz, 1H), 6.76 (t, J=8.5 Hz,2H), 5.4 (s, 2H), 5.12 (d, J=4.4 Hz, 2H), 4.5 (q, J=7.2 Hz, 2H), 1.45(t, J=7.3 Hz, 3H); LC/MS (ES⁺): 651.2 (M+1)⁺.

Example 196-{3-[5-(4-Fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxycarbonylmethoxy-phenoxymethyl}-pyridine-2-carboxylicacid

6-{2-Cyanomethoxy-3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-pyridine-2-carboxylicacid ethyl ester is dissolved in THF (1.5 mL) and MeOH (1.0 mL), LiOH (1M) (0.5 mL) is added. After stirring for 1 hour, the solvent is removedfrom the reaction mixture. A mixture of MeOH/DMSO is added to theresidue and resultant solution is filtered. The clear solution ispurified by preparative LC/MS (20-100% MeCN/H₂O) to give6-{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxycarbonylmethoxy-phenoxymethyl}-pyridine-2-carboxylicacid as white solid after removal of solvent: ¹H NMR (400 MHz, CDCl₃) δ8.21 (d, J=7.9 Hz, 1H), 8.03 (t, J=7.3 Hz, 1H), 7.81 (d, 10.1 Hz, 1H),7.8 (s, 1H), 7.55 (dd, J=8.9, 5.3 Hz, 2H), 7.0-7.1 (m, 4H), 6.92 (d, J=8Hz, 1H), 6.76 (t, J=7.5 Hz, 2H), 5.31 (s, 2H), 4.94 (d, J=7.8 Hz, 2H),4.8 (bs, 1H), 3.8 (s, 3H); LC/MS (ES⁺): (M+1) 656.3.

By repeating the procedures described in the above examples, usingappropriate starting materials, the following compounds of Formula I, asidentified in Table 1 and 2, are obtained.

TABLE 1 MS (m/z) Example Structure (M + 1)⁺ NMR 1

462.8 ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.35 (m, 1H), 7.34-7.29 (m, 4H),7.25 (dd, J₁ = 7.8 Hz, J₂ = 1.2 Hz, 1H), 7.19-7.13 (m, 3H), 7.07- 7.03(m, 1H), 6.99-6.96 (m, 2H), 6.50 (dd, J₁ = 71.6 Hz, J₂ = 71.2 Hz, 1H). 2

506.2 ¹H NMR (400 MHz, CDCl₃) δ 7.43 (s, 1H), 7.27 (d, J = 8.8, 2H),7.15 (m, 2H), 7.14 (d, J = 8.4 Hz, 2H) 6.99 (bs, 1H), 6.84 (t, J = 6.4Hz, 3H), 6.66 (d, J = 8.4 Hz, 1H), 6.53 (t, J = 8.0 Hz, 2H), 5.29 (bs,1H), 4.47 (d, J = 1.6 Hz, 2H). 3

520.3 ¹H NMR (400 MHz, CDCl₃) δ 7.63-7.62 (m, 2H), 7.57 (s, 1H),7.22-7.12 (m, 3H), 7.02 (dd, 2H, J₁ = 8.4 Hz, J₂ = 2 Hz), 6.9 (bs, 1H),6.85 (t, 2H, J = 8.4 Hz), 6.10 (s, 1H), 4.83 (d, 1H, J = 15.2 Hz), 4.68(d, 1H, J = 15.2 Hz), 3.94 (s, 3H). 4

610.9 ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H),7.67 (d, J = 7.7 Hz, 1H), 7.47-7.55 (m, 4H), 7.01-7.07 (m, 3H), 6.94 (t,J = 8.3 Hz, 2H), 6.77 (t, J = 8.5 Hz, 2H), 5.16 (s, 2H), 4.07 (s, 3H),3.94 (s, 3H). 5

597.3 ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 8 Hz, 2H), 7.53-7.58 (m,5H), 7.03-7.05 (m, 3H), 6.94- 6.95 (m, 2H), 6.77 (t, J = 8.2 Hz, 2H),5.2 (s, 2H), 4.08 (s, 3H). 6

520.2 ¹H NMR (400 MHz, CDCl₃) δ 7.55-7.51 (m, 3H), 7.12-6.99 (m, 4H),6.9 (d, J = 7.6 Hz, 2H), 6.77 (t, J = 8.4 Hz, 2H), 4.56 (s, 2H), 4.08(s, 3H), 3.26-3.2 (m, 2H), 1.02-0.99 (m, 1H), 0.57-0.52 (m, 2H), 0.25(m, 2H). 7

574.2 ¹H NMR (400 MHz, CDCl₃) δ 7.55-7.51 (m, 3H), 7.35-7.26 (m, 2H),7.05-6.96 (m, 3H), 6.85 (d, J = 8 Hz, 1H), 6.69 (t, J = 7.6 Hz, 2H),6.56 (s, 1H), 4.72 (s, 2H), 2.33 (s, 3H). 8

571.1 ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.9 (d, J = 7.6 Hz, 1H),7.7 (s, 1H), 7.6-7.5 (m, 4H) 7.35 (d, J = 7.6 Hz, 1H), 7.06 (t, J = 8.4Hz, 1H), 6.99 (t, J = 7.6 Hz, 2H), 6.88 (d, J = 8 Hz), 6.79 (t, J = 8.4Hz, 2H), 6.26 (bs, 1H), 5.33 (d, J = 7.6 Hz). 9

566.1 ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.23 (m, 3H), 7.20 (d, J = 1.9 Hz,1H), 7.10-7.05 (m, 1H), 7.03- 6.99 (m, 1H), 6.86 (d, J = 8.1 Hz, 1H),6.78-6.74 (m, 3H), 6.55 (d, J = 1.9 Hz, 1H), 6.55-6.50 (m, 2H),5.38-5.21 (m, 2H). 10

556.5 ¹H NMR (400 MHz, CDCl₃) δ 8.71 (d, J = 2.1 Hz, 1H), 7.81 (dd, J₁ =8.2 Hz, J₂ = 2.2 Hz, 1H), 7.53 (s, 1H), 7.36-7.4 (m, 2H), 7.26 (d, J =8.1 Hz, 2H), 7.18 (d, J = 8.3 Hz, 1H), 6.78 (t, J = 8.3 Hz, 2H), 6.67(dd, J₁ = 75.0 Hz, J₂ = 71.7 Hz, 1H), 2.64 (s, 3H). 11

480.0 ¹H NMR (400 MHz, CDCl₃) δ 9.02 (d, J = 2.0 Hz, 1H), 8.41 (d, J =8.6 Hz, 1H), 8.23 (dd, J₁ = 8.2 Hz, J₂ = 2.2 Hz, 1H), 7.77 (d, J = 7.5Hz, 1H), 7.65 (s, 1H), 7.62 (dd, J₁ = 7.8 Hz, J₂ = 1.3 Hz, 1H),7.45-7.53 (m, 5H), 6.97-7.01 (m, 2H), 2.79 (s, 3H). 12

442.1 ¹H NMR (400 MHz, CDCl₃) δ 7.55-7.51 (m, 3H), 7.12-6.99 (m, 4H),6.9 (d, J = 7.6 Hz, 2H), 6.77 (t, J = 8.4 Hz, 2H), 4.56 (s, 2H), 4.08(s, 3H), 3.26-3.2 (m, 2H), 1.02-0.99 (m, 1H), 0.57-0.52 (m, 2H), 0.25(m, 2H). 13

484.4 ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 7.93-7.97 (m, 1H), 7.54(s, 1H), 7.37-7.41 (m, 2H), 7.24-7.27 (m, 1H), 7.19 (d, J = 8.1 Hz, 1H),6.97 (dd, J₁ = 8.6 Hz, J₂ = 2.7 Hz, 1H), 6.78 (t, J = 8.3 Hz, 2H), 6.67(dd, J₁ = 75.0 Hz, J₂ = 71.7 Hz, 1H). 14

596.2 ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 1H), 8.48 (d, J = 7.9 Hz, 1H),8.27 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.6(dd, J₁ = 7.7 Hz, J₂ = 1.2 Hz, 1H), 7.46 (m, 1H), 7.29-7.42 (m, 3H),7.19 (q, J = 8.2 Hz, 1H), 6.76-6.81 (m, 2H). 15

594.0 ¹H NMR (400 MHz, CDCl₃) δ 11.27 (s, 1H), 8.55 (dd, J₁ = 1.2 Hz, J₂= 8 Hz, 1H), 7.96 (d, J = 8 Hz, 2H), 7.71-7.77 (m, 2H), 7.59- 7.64 (m,3H), 7.42-7.47 (m, 1H), 7.12-7.8 (m, 2H), 6.95-7.03 (m, 3H), 6.86-6.92(m, 2H), 5.2 (s, 2H), 4.77 (s, 2H), 4.07 (s, 3H). 16

611.1 ¹H NMR (400 MHz, CDCl₃) δ 7.7 (d, J = 7 Hz, 1H), 7.64 (s, 1H),7.52-7.61 (m, 4H), 7.5 (s, 1H), 7.03-7.08 (m, 2H), 7.0 (d, J = 8.2 Hz,1H), 6.95 (d, J = 7.9 Hz, 1H), 6.9 (d, J = 6.8 Hz, 1H), 6.76 (t, J = 8Hz, 2H), 6.41 (bs, 2NH), 5.21 (dd, J = 14.5, 12.8 Hz, 2H), 4.04 (s, 3H).17

540.1 ¹H NMR (400 MHz, CDCl₃) δ 11.2 (s, 1H), 8.53 (m, 1H), 7.73 (m,2H), 7.6 (s, 1H), 7.44 (t, J = 8.4 Hz, 1H), 7.15 (t, J = 8 Hz, 2H),6.9-7.1 (m, 5H), 4.58 (s, 2H), 4.14 (m, 1H), 4.06 (s, 3H), 3.69 (m, 1H),3.59 (m, 1H), 2.1 (bs, 2H), 1.23 (m, 3H). 18

651.0 ¹H NMR (400 MHz, CDCl₃) δ 8.1 (d, J = 7.9 Hz, 1H), 7.94 (t, J =7.9 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.54-7.58 (m, 3H), 7.05-7.14 (m,3H), 7.01 (d, J = 7.3 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.76 (t, J =8.5 Hz, 2H), 5.4 (s, 2H), 5.12 (d, J = 4.4 Hz, 2H), 4.5 (q, J = 7.2 Hz,2H), 1.45 (t, J = 7.3 Hz, 3H). 19

656.0 ¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, J = 7.9 Hz, 1H), 8.03 (t, J =7.3 Hz, 1H), 7.81 (d, 10.1 Hz, 1H), 7.8 (s, 1H), 7.55 (dd, J = 8.9, 5.3Hz, 2H), 7.0-7.1 (m, 4H), 6.92 (d, J = 8 Hz, 1H), 6.76 (t, J = 7.5 Hz,2H), 5.31 (s, 2H), 4.94 (d, J = 7.8 Hz, 2H), 4.8 (bs, 1H), 3.8 (s, 3H).20

597.3 ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H),7.73 (d, J = 7.6 Hz, 1H), 7.51-7.55 (m, 4H), 7.05 (m, 3H), 6.95 (t, J =8.6 Hz, 2H), 6.77 (t, J = 8.3 Hz, 2H), 5.18 (s, 2H), 4.08 (s, 3H). 21

520.3 ¹H NMR (400 MHz, CDCl₃) δ 7.54 (m, 2H), 7.5 (s, 1H), 7.0- 7.13 (m,4H), 6.92 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 6.77 (t, J = 8.3 Hz, 1H),5.78 (s, 1H), 4.58 (s, 2H), 4.06 (s, 3H). 22

447.0 ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J = 7.7 Hz, 1H), 7.73 (d, J =9.6 Hz, 1H), 7.66 (dd, J₁ = 8.7 Hz, J₂ = 5.3 Hz, 2H), 7.56 (s, 1H), 7.44(q, J = 8.0 Hz, 1H), 7.33-7.37 (m, 2H), 7.17-7.26 (m, 3H), 7.12 (t, J =8.5 Hz, 2H), 6.7 (dd, J₁ = 76 Hz, J₂ = 71 Hz, 1H). 23

518.2 ¹H NMR (400 MHz, CDCl₃) δ 7.39 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H),7.21 (d, J = 8.0 Hz, 2H), 7.02 (t, 1H), 6.82 (t, J = 8.0 Hz, 2H), 6.62(t, J = 8.0 Hz, 2H), 4.86 (d, J = 6.8 Hz, 2H), 3.78 (s, 3H). 24

483.0 ¹H NMR (400 MHz, CDCl₃) 7.54 (dd, J₁ = 8.7 Hz, J₂ = 5.2 Hz, 2H),7.5 (s, 1H), 7.4 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.24 (t,J = 7.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 8.5 Hz, 2H),6.77 (t, J = 8.4 Hz, 2H), 6.68 (dd, J₁ = 75 Hz, J₂ = 72 Hz, 1H). 25

443.0 ¹H NMR (400 MHz, CDCl₃) 7.4- 7.44 (m, 2H), 7.23-7.32 (m, 3H),7.12-7.16 (m, 5H), 7.08 (t, J = 7.9 Hz, 1H), 6.93 (t, J = 8.5 Hz, 2H),6.6 (dd, J₁ = 71 Hz, J₂ = 76 Hz, 1H), 2.24 (s, 3H). 26

518.0 ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.35 (m, 3H), 7.22 (d, 2H, J = 8.8Hz), 7.05 (t, 1H, J = 8 Hz), 6.85-6.80 (m, 2H), 6.63 (m, 2H), 4.87 (d,2H, J = 7.2 Hz), 3.79 (s, 3H). 27

509.3 ¹H NMR (400 MHz, CDCl₃) δ 7.88-7.85 (m, 2H), 7.71 (t, 1H, J = 7.6Hz), 7.67-7.62 (m, 2H), 7.55 (s, 1H), 7.11 (t, 2H, J = 11.6 Hz), 7.03(t,1H, J = 8 Hz), 6.90 (dd, 1H, J₁ = 8 Hz, J₂ = 1.6 Hz), 6.82 (dd, 1H, J₁ =7.6 Hz, J₂ = 1.2 Hz), 4.03 (s, 3H), 3.88 (s, 3H). 28

490.2 ¹H NMR (400 MHz, CDCl₃) δ 7.58 (s, 1H), 7.49 (m, 2H), 7.33 (dd, J₁= 7.6 Hz, J₂ = 1.2 Hz, 1H), 7.25 (td, J₁ = 8.4 Hz, J₂ = 1.2 Hz, 1H),7.13 (bs, 1H), 6.99 (m, 3H), 6.81 (d, J = 8 Hz, 1H), 6.68 (t, J = 8.4Hz, 2H), 5.76 (bs, 1H), 4.61 (d, J = 1.6 Hz, 2H). 29

459.0 ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, 2H, J = 8 Hz), 7.61-7.57 (m,3H), 7.39-7.30 (m, 4H), 7.29- 7.26 (m, 2H), 7.21-7.16 (m, 2H), 6.7 (dd,1H, J₁ = 76 Hz, J₂ = 71.2 Hz). 30

507.3 ¹H NMR (400 MHz, CDCl₃) δ 7.53 (dd, J₁ = 8.7 Hz, J₂ = 5.3 Hz, 2H),7.5 (s, 1H), 7.03-7.08 (m, 3H), 6.94 (d, J = 8.4 Hz, 2H), 6.77 (t, J =8.5 Hz, 2H), 4.15 (t, J = 4.5 Hz, 2H), 4.05 (s, 3H), 3.98-4.02 (m, 2H).31

610.3 ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, 1H, J = 8 Hz), 7.95 (d, 1H, J =8 Hz), 7.65 (s, 1H), 7.53- 7.42 (m, 4H), 7.13 (t, 1H, J = 8 Hz),7.03-6.94 (m, 4H), 6.77 (bs, 2H), 5.7 (s, 2H), 3.90 (s, 3H). 32

504.1 ¹H NMR (400 MHz, CDCl₃) δ 7.63 (s, 1H), 7.6-7.55 (m, 2H), 7.41-7.39 (m, 1H), 7.35-7.31 (m, 1H), 7.25-7.21 (bs, 1H), 7.11-7.04 (m, 3H),6.87 (d, J = 8.4 Hz, 1H), 6.76 (t, J = 8.4 Hz, 1H), 4.69 (d, J = 7.2 Hz,2H), 2.81 (d, J = 4.8 Hz, 3H). 33

591.2 ¹H NMR (400 MHz, CDCl₃) δ 7.36 (m, 4H), 6.89-6.59 (m, 6H), 4.38(s, 2H), 3.8 (s, 3H), 3.44 (m, 1H), 3.32 (m, 1H), 2.29 (s, 1H). 34

587.1 ¹H NMR (400 MHz, CDCl₃) δ 7.53 (dd, J₁ = 8.7 Hz, J₂ = 5.3 Hz, 2H),7.5 (s, 1H), 7.16 (d, J = 3.4 Hz, 1H). 7.02-7.07 (m, 3H), 6.94-6.97 (m,2H), 6.77 (t, J = 8.4 Hz, 2H), 6.54 (d, J = 3.4 Hz, 1H), 5.12 (s, 2H),4.04 (s, 3H), 3.9 (s, 3H). 35

588.1 ¹H NMR (400 MHz, CDCl₃) δ 7.53 (dd, J₁ = 8.9 Hz, J₂ = 5.2 Hz, 2H),7.5 (s, 1H), 7.3 (d, J = 3.5 Hz, 1H). 7.03-7.07 (m, 3H), 6.96 (d, J =8.3 Hz, 2H), 6.77 (t, J = 8.3 Hz, 2H), 6.58 (d, J = 3.5 Hz, 1H), 5.15(s, 2H), 4.05 (s, 3H), 2.9 (bs, 1H). 36

601.0 ¹H NMR (400 MHz, CDCl₃) δ 7.53 (dd, J₁ = 8.7 Hz, J₂ = 5.3 Hz, 2H),7.5 (s, 1H), 7.16 (d, J = 3.4 Hz, 1H). 7.02-7.07 (m, 3H), 6.94-6.97 (m,2H), 6.77 (t, J = 8.4 Hz, 2H), 6.54 (d, J = 3.4 Hz, 1H), 5.12 (s, 2H),4.04 (s, 3H), 3.9 (s, 3H). 37

518.0 ¹H NMR (400 MHz, CDCl₃) δ 7.39 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H),7.21 (d, J = 8.0 Hz, 2H), 7.02 (t, 1H), 6.82 (t, J = 8.0 Hz, 2H), 6.62(t, J = 8.0 Hz, 2H), 4.86 (d, J = 6.8 Hz, 2H), 3.78 (s, 3H). 38

605.2 ¹H NMR (400 MHz, CDCl₃) δ 7.74- 7.7 (m, 3H), 7.3-7.18 (m, 4H),7.11 (d, J = 8.4 Hz, 1H), 6.97 (t, J₁ = 8.4 Hz, J₂ = 2 Hz), 6.33 (bs,1H), 4.79 (s, 2H), 4.27 (s, 3H), 3.74- 3.54 (m, 4H), 2.3 (s, 1H), 2.15(s, 3H). 39

490.0 ¹H NMR (400 MHz, CDCl₃) δ 7.63-7.62 (m, 2H), 7.57 (s, 1H),7.22-7.12 (m, 3H), 7.02 (dd, 2H, J₁ = 8.4 Hz, J₂ = 2 Hz), 6.9 (bs, 1H),6.85 (t, 2H, J = 8.4 Hz), 6.10 (s, 1H), 4.83 (d, 1H, J = 15.2 Hz), 4.68(d, 1H, J = 15.2 Hz), 3.94 (s, 3H). 40

598.2 ¹H NMR (400 MHz, CDCl₃) δ 9.33 (bs, 1H), 9.02 (s, 1H), 8.77 (d, J= 6 Hz, 1H), 8.31 (d, J = 6 Hz, 1H), 7.63-7.60 (m, 3H), 7.22-7.12 (m,4H), 7.04 (d, J = 8 Hz, 1H), 6.86 (t, J = 8 Hz, 2H), 4.8 (s, 2H), 4.23(s, 3H). 41

506.0 ¹H NMR (400 MHz, CDCl₃) δ 7.43 (s, 1H), 7.27 (d, J = 8.8, 2H),7.15 (m, 2H), 7.14 (d, J = 8.4 Hz, 2H) 6.99 (bs, 1H), 6.84 (t, J = 6.4Hz, 3H), 6.66 (d, J = 8.4 Hz, 1H), 6.53 (t, J = 8.0 Hz, 2H), 5.29 (bs,1H), 4.47 (d, J = 1.6 Hz, 2H). 42

595.2 ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.36 (m, 3H), 7.32(d, J = 8 Hz,2H), 7.2(d, J = 7.6 Hz, 2H), 7.16 (m, 1H), 6.92-6.85 (m, 4H), 6.72-6.58(bs, 3H), 5.05 (s, 2H), 3.59 (s, 3H), 3.53 (s, 2H). 43

602.1 ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 7.53 (m, 2H), 7.49 (s,1H), 7.02-7.07 (m, 4H), 6.97 (dd, J₁ = 6.0 Hz, J₂ = 3.2 Hz, 1H), 6.77(t, J = 8.2 Hz, 2H), 5.25 (d, J = 1.8 Hz, 2H), 4.05 (s, 3H), 3.94 (s,3H). 44

588.1 ¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H),7.52 (d, J = 8.6 Hz, 1H), 7.49 (s, 1H), 7.01-7.07 (m, 4H), 6.98 (d, J =7.2 Hz, 1H), 6.77 (t, J = 8.2 Hz, 2H), 5.26 (s, 2H), 4.05 (s, 3H). 45

588.1 ¹H NMR (400 MHz, CDCl₃) δ 7.54 (dd, J₁ = 8.8 Hz, J₂ = 5.2 Hz, 2H),7.5 (s, 1H), 7.03-7.09 (m, 3H), 7.0 (dd, J₁ = 6.7 Hz, J₂ = 1.2 Hz, 1H),6.95 (dd, J₁ = 8.0 Hz, J₂ = 1.2 Hz, 1H), 6.84 (s, 1H), 6.77 (t, J = 8.2Hz, 2H), 5.27 (s, 2H), 4.05 (s, 3H). 46

587.1 ¹H NMR (400 MHz, CDCl₃) 7.51- 7.55 (m, 2H), 7.5 (s, 1H), 7.45 (d,J = 1.9 Hz, 1H), 6.98-7.07 (m, 5H), 6.94 (dd, J₁ = 7.1 Hz, J₂ = 2.0 Hz,1H), 6.77 (t, J = 8 Hz, 2H), 5.46 (d, J = 12.7 Hz, 2H), 5.38 (d, J =12.8 Hz, 1H), 4.04 (s, 3H). 47

536.1 ¹H NMR (400 MHz, CDCl₃) δ 7.79-7.77 (m, 2H), 7.73-7.69 (m, 2H),7.55 (dd, J₁ = 6.1 Hz, J₂ = 1.5 Hz, 1H), 7.50-7.45 (m, 1H), 7.24- 7.18(m, 3H), 7.02 (d, J = 8.1 Hz, 1H), 6.92-6.87 (m, 2H), 4.89 (d, J = 6.8Hz, 2H), 4.66-4.63 (m, 1H), 4.54-4.51 (m, 1H), 3.84-3.62 (m, 2H). 48

576.2 ¹H NMR (400 MHz, CDCl₃) δ 7.64-7.61 (m, 2H), 7.59 (s, 1H),7.21-7.13 (m, 3H), 7.09 (dd, J₁ = 6.5 Hz, J₂ = 1.1 Hz, 1H), 7.05 (bs,1H), 7.01 (dd, J₁ = 6.7 Hz, J₂ = 1.3 Hz, 1H), 6.87 (m, 2H), 4.69 (s,2H), 4.15 (s, 3H), 3.29 (t, J = 6.6 Hz, 2H), 1.98-1.88 (m, 1H), 1.03 (d,J = 6.6 Hz, 6H). 49

587.1 ¹H NMR (400 MHz, CDCl₃) δ 7.54 (d, J = 8.8 Hz, 2H), 7.53 (t, J =8.7 Hz, 1H), 7.5 (s, 1H), 7.31 (d, J = 3.5 Hz, 1H), 7.03-7.07 (m, 3H),6.97 (d, J = 2.2 Hz, 1H), 6.95 (s, 1H), 6.77 (t, J = 8.3 Hz, 2H), 6.59(d, J = 3.5 Hz, 1H), 5.15 (d, 2H), 4.05 (s, 3H). 50

598.2 ¹H NMR (400 MHz, CDCl₃) δ 8.2 (d, J = 7.7 Hz, 1H), 8.03 (t, J =7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.52-7.56 (m, 3H), 7.03-7.08 (m,3H), 6.97 (d, J = 7.9 Hz, 1H), 6.92 (d, J = 7.1 Hz, 1H), 6.77 (t, J =8.4 Hz, 2H), 5.32 (s, 2H), 4.11 (s, 3H). 51

625.2 ¹H NMR (400 MHz, CDCl₃) δ 8.91 (bs, 1H), 7.82 (s, 1H), 7.46- 7.42(m, 3H), 7.00-6.85 (m, 5H), 6.69-6.65 (m, 3H), 4.58 (s, 2H), 4.05 (s,3H), 2.34 (s, 3H), 2.25 (s, 3H). 52

539.1 ¹H NMR (400 MHz, CDCl₃) δ 7.70 (dd, J₁ = 5.2 Hz, J₂ = 8.8 Hz, 2H),7.28 (m, 2H), 7.11 (m, 2H), 6.9 (m, 2H), 6.74 (dd, 1H), 6.56 (d, J = 3.6Hz, 1H), 5.11 (s, 2H), 3.98 (s, 3H), 3.24 (m, 1H), 2.08 (m, 1H),1.90-1.83 (m, 3H), 1.72 (m, 1H), 1.59-1.3 (m, 5H). 53

493.1 ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 6.4 Hz, 1H), 7.60 (m, 4H),7.45-7.36 (m, 6H), 7.04 (m, 2H), 6.22 (m, 1H), 5.58 (d, J = 17.2 Hz,1H), 5.44 (d, J = 10.4 Hz, 1H), 4.77 (d, J = 4.8 Hz, 2H), 2.27 (s, 3H).54

410.0 ¹H NMR (400 MHz, CDCl₃) δ 11.22 (bs, 1H), 8.56 (dd, J = 8.4 Hz,1H), 8.14 (dd, J₁ = 1.6 Hz, J₂ = 5.2 Hz, 1H), 7.72 (m, 2H), 7.47 (m,2H), 7.38 (dd, J₁ = 1.2 Hz, J₂ = 7.2 Hz, 1H), 7.14 (t, J = 8.4 Hz, 2H),7.01 (m, 2H), 6.86 (dd, J₁ = 5.2 Hz, J₂ = 7.2 Hz, 1H), 4.08 (s, 3H). 55

501.3 ¹H NMR (400 MHz, CDCl₃) δ 7.53 (dd, J₁ = 8.8 Hz, J₂ = 5.2 Hz, 2H),7.5 (s, 1H), 7.04-7.07 (m, 4H), 6.95 (d, J = 6.8 Hz, 2H), 6.77 (t, J =8.2 Hz, 2H), 4.76 (d, J = 2.3 Hz, 2H), 4.05 (s, 3H), 2.53 (t, J = 2.4Hz, 1H). 56

448.0 ¹H NMR (400 MHz, CDCl₃) δ 8.19 (dd, J₁ = 1.6 Hz, J₂ = 4.8 Hz, 1H),7.56 (m, 3H), 7.41 (s, 1H), 7.09 (t, J = 8.4 Hz, 2H), 6.95 (dd, J₁ = 5.2Hz, J₂ = 7.2 Hz, 1H), 6.83 (bs, 2H), 4.11 (s, 3H). 57

472.0 ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1H), 8.82 (s, 1H), 8.47 (s,1H), 7.64-7.67 (m, 2H), 7.53 (s, 1H), 7.32 (dt, J₁ = 7.3 Hz, J₂ = 1.5Hz, 1H), 7.07-7.14 (m, 3H), 6.92- 6.96 (m, 2H), 3.94 (s, 3H). 58

409.1 ¹H NMR (400 MHz, CDCl₃) δ 8.92 (d, J = 1.3 Hz, 1H), 8.27 (dd, J₁ =8.3 Hz, J₂ = 1.7 Hz, 1H), 8.18 (dd, J₁ = 5.1 Hz, J₂ = 1.7 Hz, 1H), 7.78(d, J = 7.8 Hz, 1H), 7.68 (d, J = 9.4 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H),7.52 (s, 1H), 7.49 (dd, J₁ = 8.1 Hz, J₂ = 2.5 Hz, 1H), 7.39 (dd, J₁ =7.4 Hz, J₂ = 1.5 Hz, 1H), 7.29 (dd, J₁ = 8.3 Hz, J₂ = 2.5 Hz, 1H), 6.91(dd, J₁ = 7.4 Hz, J₂ = 5.1 Hz, 1H), 4.08 (s, 3H), 2.81 (s, 3H). 59

405.1 ¹H NMR (400 MHz, CDCl₃) δ 8.76 (m, 1H), 8.21 (m, 2H), 7.39-7.56(m, 5H), 7.29 (d, J = 6.9 Hz, 1H), 6.95 (dd, J₁ = 7.3 Hz, J₂ = 5.2 Hz,1H), 4.08 (s, 3H), 2.81 (s, 3H), 2.38 (s, 3H). 60

407.1 ¹H NMR (400 MHz, CDCl₃) δ 9.04 (d, J = 1.0 Hz, 1H), 8.39 (d, J =8.1 Hz, 1H), 8.35 (dd, J₁ = 8.3 Hz, J₂ = 1.6 Hz, 1H), 8.20 (dd, J₁ = 5.0Hz, J₂ = 1.4 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.58 (s, 1H), 7.49 (t, J= 8.3 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 7.0(d, J = 7.4 Hz, 1H), 6.92 (dd, J₁ = 7.4 Hz, J₂ = 5.1 Hz, 1H), 4.1 (s,3H), 2.85 (s, 3H). 61

424.1 ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H),8.15 (dd, J₁ = 8.3 Hz, J₂ = 2.0 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 8.5Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.07 (dd, J₁ = 8.5 Hz, J₂ = 6.3 Hz,1H), 7.02 (d, J = 8.6 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.69 (dd, J₁ =10.5 Hz, J₂ = 2.2 Hz, 1H), 6.62 (dd, J₁ = 8.3 Hz, J₂ = 2.3 Hz, 1H), 3.94(s, 3H), 2.74 (s, 3H). 62

425.5 ¹H NMR (400 MHz, CDCl₃) δ 8.34 (s, 1H), 7.93 (dd, J₁ = 8.8 Hz, J₂= 2.2 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.37 (t, J = 7.5Hz, 1H), 7.26-7.28 (m, 2H), 7.15 (dd, J₁ = 8.4 Hz, J₂ = 6.4 Hz, 1H),6.92 (dd, J₁ = 8.3 Hz, J₂ = 1.8 Hz, 1H), 6.64-6.71 (m, 2H), 3.93 (s,3H), 2.39 (s, 3H). 63

465.4 ¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, J = 2.3 Hz, 1H), 7.94 (dt, J₁ =8.5 Hz, J₂ = 2.5 Hz, 1H), 7.46 (s, 1H), 7.18 (dt, J₁ = 8.1 Hz, J₂ = 2.3Hz, 1H), 6.95 (dd, J₁ = 8.6 Hz, J₂ = 2.9 Hz, 1H), 6.78 (bm, 2H),6.65-6.7 (m, 2H), 6.76-6.82 (m, 2H), 3.93 (s, 3H). 64

449 ¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, J = 2.2 Hz, 1H), 8.17 (dd, J₁ =5.1 Hz, J₂ = 1.5 Hz, 1H), 7.93 (dd, J₁ = 8.4 Hz, J₂ = 1.8 Hz, 1H), 7.49(dd, J₁ = 7.5 Hz, J₂ = 1.3 Hz, 1H), 7.41 (s, 1H), 6.92-6.97 (m, 2H),6.76-6.82 (m, 2H), 4.07 (s, 3H). 65

409.1 ¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J = 1.6 Hz, 1H), 8.18 (dd, J₁ =5.0 Hz, J₂ = 1.6 Hz, 1H), 7.93 (dd, J₁ = 8.6 Hz, J₂ = 2.4 Hz, 1H), 7.47(s, 2H), 7.45 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.27-7.31 (m, 2H),6.9-6.93 (m, 2H), 4.07 (s, 3H), 2.4 (s, 3H). 66

416.2 ¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 8.62 (d, J = 4.8 Hz, 1H),7.82 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.26-7.39 (m, 5H),7.17 (m, 1H). 67

416.3 ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J = 5.3 Hz, 1H), 7.68 (d, J =8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.32 (s, 1H), 7.31 (d, J = 6.7Hz, 1H), 6.9 (dd, , J = 7.5, 5.1 Hz, 1H), 4.1 (s, 3H), 3.31 (t, J = 11.1Hz, 1H), 2.16 (d, , J = 11.4 Hz, 1H), 1.92 (m, 3H), 1.79 (d, J = 12.3Hz, 1H), 1.32-1.64 (m, 5H). 68

464.2 ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J = 6.1 Hz, 1H), 7.49 (d, J =7.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.37 (s, 1H), 7.33 (d, J = 8.7Hz, 1H), 6.92 (dd, J = 7.3, 4.8 Hz, 1H), 6.79 (m, 2H), 4.1 (s, 3H). 69

488.0 1H NMR (400 MHz, CDCl₃) δ 9.26 (s, 1H), 8.73 (s, 1H), 8.54 (s,1H), 7.48 (d, J = 8.4 Hz, 2H), 7.38 (s, 1H), 7.26 (d, J = 8.4 Hz, 2H),7.19 (t, J = 7.2 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.86 (m, 2H) 3.8 (s,3H). 70

431.1 1H NMR (400 MHz, CDCl₃) δ 7.61 (t, J = 8.4 Hz, 1H), 7.4 (m, 1H),7.23 (dd, J = 16.9, 8 Hz, 1H), 7.17 (s, 1H), 6.73-6.79 (m, 2H), 6.66 (d,J = 7.4 Hz, 1H), 5.99 (d, J = 4.6 Hz, 2H), 3.17 (d, J = 11.8 Hz, 1H),1.99 (d, , J = 11.4 Hz, 1H), 1.84 (m, 3H), 1.72 (d, J = 12.8 Hz, 1H),1.19-1.65 (m, 5H). 71

436.0 ¹H NMR (400 MHz, CDCl₃) δ 8.77 (s, 1H), 8.64 (s, 1H), 7.87 (d, J =7.5 Hz, 1H), 7.4-7.45 (m, 2H), 7.28-7.32 (m, 2H), 7.21 (dd, J = 17.4,9.1 Hz, 1H), 6.77 (t, J = 8.2 Hz, 2H). 72

411.3 ¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 7.6 Hz, 1H), 7.77 (m, 1H),7.67 (m, 2H), 7.55 (s, 1H), 7.48 (m, 1H), 7.32 (m, 1H), 7.26 (m, 2H),7.15 (d, J = 7.6 Hz, 1H), 7.09 (t, J = 8.4 Hz, 2H), 6.95 (m, 2H), 3.95(s, 3H). 73

451.1 ¹H NMR (400 MHz, CDCl₃) δ 7.65 (dd, J₁ = 1.6 Hz, J₂ = 1.6 Hz, 1H),7.56 (m, 4H), 7.35 (m, 4H), 7.02 (t, J = 8.4 Hz, 2H), 6.97 (m, 2H), 3.95(s, 3H), 2.12 (s, 3H). 74

425.3 ¹H NMR (400 MHz, CDCl₃) δ 7.9 (m, 2H), 7.66 (m, 2H), 7.54 (s, 1H),7.32 (m, 1H), 7.15 (m, 4H), 6.95 (m, 2H), 3.97 (s, 3H), 2.35 (s, 3H). 75

481.2 ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.48 (m, 3H), 7.34 (d, J = 8.7 Hz,1H), 7.29 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.98-7.11 (m,3H), 6.78 (t, J = 8.5 Hz, 2H), 4.11 (d, J = 2.7 Hz, 3H). 76

452.2 ¹H NMR (400 MHz, CDCl₃) δ 8.4 (d, J = 3.1 Hz, 1H), 7.66 (d, J =7.9 Hz, 1H), 7.53 (dd, J = 9.9, 5.5 Hz, 2H), 7.48 (s, 1H), 7.31 (dd, J =8, 4.6 Hz, 1H), 7.07 (t, J = 8.6 Hz, 2H), 6.81 (t, J = 8.5 Hz, 2H). 77

485.2 ¹H NMR (400 MHz, CDCl₃) δ 8.1 (d, J = 7.8 Hz, 1H), 7.43-7.49 (m,4H), 7.38 (d, J = 8.9 Hz, 2H), 7.25-7.3 (m, 2H), 7.16 (dd, J = 8.2, 6.3Hz, 1H), 6.6-6.7 (m, 2H), 3.92 (s, 3H), 2.39 (s, 3H). 78

463.2 ¹H NMR (400 MHz, CDCl₃) δ 7.54 (dd, J = 8.9, 5.3 Hz, 2H), 7.47 (s,1H), 7.01-7.08 (m, 3H), 6.93 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 7.9 Hz,1H), 6.77 (t, J = 8.4 Hz, 2H), 5.3 (bs, 1H), 4.03 (s, 3H). 79

400.1 ¹H NMR (400 MHz, CDCl₃): δ 8.09 (dd, J₁ = 1.6 Hz, J₂ = 5.2 Hz,1H), 7.69 (dd, J₁ = 5.2 Hz, J₂ = 8.8 Hz, 2H), 7.24 (dd, J₁ = 1.2 Hz, J₂= obscureδ by CDCl₃, 1H), 7.2 (s, 1H), 7.11 (t, J = 8.8 Hz, 2H), 6.83(dd, J₁ = 4.8 Hz, J₂ = 7.2 Hz, 1H), 4.03 (s, 3H), 3.21-3.29 (m, 1H),2.11 (d, J = 12 Hz, 1H), 1.81-1.92 (m, 3H), 1.74 (d, J = 12 Hz, 1H),1.21-1.67 (m, 7H). 80

557.2 ¹H NMR (400 MHz, CDCl₃) δ 8.03(s, 1H), 7.92 (d, J = 8 Hz, 1H),7.57 (d, J = 7.6 Hz, 1H), 7.43 (s, 1H), 7.37 (t, J = 6.8 Hz, 3H), 7.28(d, J = 7.2 Hz, 1H), 7.19 (s, 1H), 7.11 (m, 2H), 6.89 (m, 3H), 6.79 (m,2H), 5.02 (s, 2H), 3.94 (s, 3H), 2.22 (s, 3H). 81

548.2 ¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H),7.72 (m, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.34(s, 1H), 7.11 (t, J = 8.4 Hz, 2H), 6.94 (t, J = 8 Hz, 1H), 6.88 (dd, J₁= 8.0 Hz, J₂ = 1.2 Hz, 1H), 6.72 (dd, J₁ = 8.0 Hz, J₂ = 1.2 Hz, 1H),6.22 (s, 1H), 5.81 (bs, 2H), 5.14 (s, 2H), 4.01 (s, 3H), 3.28 (m, 1H),2.1 (m, 1H), 1.91 (m, 3H), 1.77 (m, 1H), 1.59 (m, 4H), 1.29 (m, 1H). 82

591.1 ¹H NMR (400 MHz, CDCl₃) δ 9.46 (s, 1H), 9.01 (s, 1H), 8.71 (s,1H), 7.89 (m, 2H), 7.73 (s, 1H), 7.34 (m, 3H), 7.15 (m, 2H), 4.78 (s,2H), 4.25 (s, 2H), 3.93 (m, 2H). 83

520.2 ¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, J = 8 Hz, 1H), 7.82 (m, 2H),7.68 (s, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 8.4 Hz, 2H), 7.08(m, 4H), 6.95 (m, 1H), 6.21 (s, 1H), 5.23 (s, 2H), 4.11 (s, 3H), 2.52(s, 3H. 84

465.0 ¹H NMR (400 MHz, CDCl₃) δ 7.54 (m, 2H), 7.42 (s, 1H), 7.21 (m,1H), 7.06 (m, 2H), 6.83 (m, 2H), 6.69 (m, 2H), 3.92 (s, 3H). 85

513.0 ¹H NMR (400 MHz, CDCl₃) δ 7.59 (m, 2H), 7.48 (s, 1H), 7.41 (m,2H), 7.26 (m, 1H), 7.18 (d, J = 8 Hz, 1H), 7.11 (m, 3H), 6.68 (dd, J1 =75.6 Hz, J2 = 4.4 Hz, 1H), 4.09 (s, 1H). 86

449.1 ¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J = 2.7 Hz, 1H), 8.14 (d, J =5.1 Hz, 1H), 7.77 (dd, J = 8.7, 4.1 Hz, 1H), 7.5 (d, J = 8.9 Hz, 1H),7.41 (dt, J = 8.5, 2.7 Hz, 1H), 7.3 (s, 1H), 6.91 (dd, J = 7.7, 5 Hz,1H), 6.79 (m, 2H), 4.06 (m, 3H). 87

466.0 ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J = 4.1 Hz, 1H), 7.68 (dd, J =8.9, 4.4 Hz, 1H), 7.31 (dt, J = 8, 2.9 Hz, 1H), 7.17 (s, 1H), 7.1 (dd, J= 9, 6.1 Hz, 1H), 6.69 (m, 2H), 6.53-6.58 (m, 2H), 3.82 (s, 3H). 88

498.9 ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1H), 8.82 (s, 1H), 8.48 (t, J =2 Hz, 1H), 7.67 (dd, J₁ = 5.2 Hz, J₂ = 8.8 Hz, 2H), 7.52 (s, 1H), 7.39(apparent t, J = 7.6 Hz, 1H), 7.06-7.16 (m, 3H), 7.05 (d, J = 8.4 Hz,1H), 4.92 (dd, J₁ = 16 Hz, J₂ = 27 Hz, 2H). 89

425.0 ¹H NMR (400 MHz, CDCl₃) δ 11.23 (s, 1H), 8.54 (dd, J1 = 0.8 Hz, J2= 8.4 Hz, 1H), 7.73 (dd, J1 = 5.2 Hz, J2 = 8.8 Hz, 2H), 7.59 (s, 1H),7.44 (apparent t, J = 7.2 Hz, 1H), 7.15 (t, J = 7.6 Hz, 2H),6.89-7.03-7.16 (m, 4H), 6.81 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H), 5.49(s, 1H), 4.03 (s, 3H). 90

566.1 ¹H NMR (400 MHz, CDCl₃) δ 11.14 (d, J = 3.6 Hz, 1H), 8.44 (dt, J =1.6 Hz, J₂ = 8.4 Hz, 1H), 7.63 (dd, J₁ = 5.2 Hz, J₂ = 8 Hz, 2H), 7.51(d, J = 2 Hz, 1H), 7.34 (apparent t, J = 7.2 Hz, 1H), 7.04 (t, J = 8.4Hz, 2H), 6.75-6.99 (m, 6H), 4.46 (d, J = 1.61 Hz, 2H), 3.97 (s, 3H),3.86-3.94 (m, 1H), 3.69- 3.77 (m, 1H), 3.61-3.67 (m, 1H), 3.47-3.56 (m,1H), 3.17-3.29 (m, 1H), 1.71-1.92 (m, 3H), 1.38-1.48 (m partiallyobscureδ by H2O, 1H). 91

396.0 ¹H NMR (400 MHz, CDCl₃) δ 7.87 (m, 2H), 7.66 (s, 1H), 7.61 (m,1H), 7.4 (m, 1H), 7.26 (m, 3H), 7.05 (m, 2H) 6.95 (m, 1H), 6.36 (m, 1H),4.05 (s, 6H). 92

414.0 ¹H NMR (400 MHz, CDCl₃) δ 7.74 (m, 2H), 7.48 (m, 2H), 7.13 (m,3H), 6.83 (s, 1H), 6.65 (dd, J₁ = 10.8 Hz, J₂ = 2.0 Hz, 1H), 6.59 (m,1H), 3.92 (s, 6H).

TABLE 2 MS (m/z) Example Structure (M + 1)⁺  93

503.0  94

529.1  95

513.0  96

509.2  97

502.2  98

479.0  99

479.3 100

626.3 101

611.2 102

465.2 103

447.2 104

445.2 105

445.2 106

447.3 107

447.3 108

447.3 109

443.3 110

445.2 111

598.2 112

461.2 113

558.2 114

481.0 115

495.0 116

480.0 117

562.1 118

589.9 119

499.2 120

459.3 121

425.3 122

441.2 123

410.2 124

451.2 125

409.2 126

443.2 127

461.2 128

547.1 129

479.2 130

514.9 131

493.0 132

463.0 133

639.3 134

476.8 135

532.3 136

479.0 137

459.0 138

490.1 139

563.2 140

424.0 141

429.0 142

410.0 143

549.2 144

556.2 145

621.1 146

561.1 147

472.9 148

611.3 149

625.1 150

517.3 151

558.3 152

574.4 153

590.4 154

567.3 155

559.1 156

518.2 157

583.0 158

445.1 159

465.1 160

530.2 161

526.2 162

518.2 163

578.2 164

549.1 165

571.3 166

587.2 167

598.1 168

627.1 169

627.1 170

566.2 171

472.0 172

588.1 173

612.2 174

563.2 175

623.2 176

599.1 177

430.1 178

417.1 179

425.0 180

429.1 181

435.1 182

421.0 183

648.2 184

573.1 185

615.2 186

696.2 187

544.2 188

647.2 189

559.1 190

654.2 191

653.2 192

491.0 193

413.1 194

568.2 195

538.2 196

522.1 197

587.2 198

522.1 199

524.2 200

538.2 201

568.1 202

585.2 203

528.0 204

604.2 205

575.1 206

670.2 [M + 23] 207

712.2 208

582.0 209

580.0 210

538.2 211

540.1 212

550.2 213

553.1 214

524.2 215

539.1 216

606.2 217

578.1 218

578.1 219

524.0 220

584.2 221

659.1 222

617.1 223

640.2 [M + 23] 224

603.1 225

641.1 226

552.1 227

587.1 228

606.1 229

614.1 230

591.1 231

478.0 232

484.0 233

550.0 234

544.9 235

542.1 236

534.1 237

602.1 238

675.2 239

445.0 240

495.1 241

596.1 242

596.2 243

632.1 244

581.1 245

564.1 246

445.0 247

530.0 248

526.1 249

518.1 250

596.1 251

578.1 252

560.1 253

591.0 254

531.0 255

546.2 256

560.2 257

537.1 258

532.1 259

471.1 260

468.2 261

472.2 262

550.2 263

679.2 264

588.0 265

583.0 266

436.0 267

424.1 268

502.0 269

477.0 270

547.1 271

542.0 272

454.1 273

689.1 274

620.2 275

579.2 276

668.2 277

645.2 278

551.1 279

619.2 280

567.1 281

469.1 282

520.1 283

448.0 284

592.0 285

584.1 286

662.0 287

664.0 288

579.1 289

575.0 290

567.1 291

617.2 292

611.2 293

569.1 294

489.0 295

449.1 296

491.0 297

487.0 298

441.0 299

424.0 300

640.0 301

580.1 302

596.1 303

623.1 304

586.0 305

597.0 306

556.0 307

604.1 308

562.0 309

423.1 310

427.1 311

495.1 312

490.0 313

482.0 314

442.1 315

473.0 316

430.1 317

413.1 318

552.0 319

560.1 320

626.1 321

608.0 322

628.0 323

462.0 324

430.0 325

430.0 326

448.0 327

412.1 328

433.9 329

394.0 330

493.0 331

443.0 332

445.0 333

423.2 334

427.0 335

415.1 336

478.0 337

480.0 338

412.1 339

412.0 340

444.1 341

424.1 342

408.1 343

422.1 344

454.1 345

423.3 346

427.0 347

463.0 348

458.0 349

443.0 350

452.0 351

448.0 352

412.0 353

408.3 354

397.1 355

466.1 356

398.0 357

438.0 358

593.0 359

428.0 360

559.1 361

632.0 362

596.0 363

468.2 364

428.0 365

407.1 366

407.1 367

447.0 368

425.3 369

493.0 370

481.0 371

467.0 372

566.2 373

566.0 374

569.0 375

641.0 376

551.0 377

589.1 378

583.1 379

563.1 380

547.0 381

485.0 382

441.0 383

440.0 384

481.0 385

477.0 386

467.0 387

471.0 388

467.0 389

490.2 390

561.1 391

575.1 392

551.1 393

536.1 394

576.1 395

627.1 396

609.0 397

591.1 398

629.0 399

425.3 400

495.1 401

455.1 402

479.0 403

439.0 404

443.0 405

427.0 406

411.3 407

461.0 408

558.1 409

575.0 410

598.0 411

617.0 412

536.1 413

411.0 414

429.0 415

560.1 416

471.1 417

429.1 418

393.1 419

429.1 420

429.1 421

479.0 422

399.1 423

443.2 424

463.2 425

477.3 426

545.1 427

461.0 428

479.0 429

612.0 430

561.1 431

540.1 432

540.1 433

578.1 434

611.2 435

434.2 436

488.2 437

457.3 438

477.2 439

495.2 440

477.3 441

475.2 442

477.3 443

473.3 444

586.1 445

568.1 446

582.2 447

602.1 448

554.1 449

556.1 450

554.1 451

568.1 452

540.1 453

429.2 454

447.2 455

540.1 456

584.2 457

554.1 458

540.1

Assay 1 Transcriptional Assay

Transfection assays are used to assess the ability of compounds of theinvention to modulate the transcriptional activity of the LXRs. Briefly,expression vectors for chimeric proteins containing the DNA bindingdomain of yeast GAL4 fused to the ligand-binding domain (LBD) of eitherLXRα or LXRβ are introduced via transient transfection into mammaliancells, together with a reporter plasmid where the luciferase gene isunder the control of a GAL4 binding site. Upon exposure to an LXRmodulator, LXR transcriptional activity varies, and this can bemonitored by changes in luciferase levels. If transfected cells areexposed to an LXR agonist, LXR-dependent transcriptional activityincreases and luciferase levels rise.

293T human embryonic kidney cells (8×10⁶) are seeded in a 175 cm² flask2 days prior to the start of the experiment in 10% FBS, 1%Penicillin/Streptomycin/Fungizome, DMEM Media. The transfection mixturefor chimeric proteins is prepared using GAL4-LXR LBD expression plasmid(4 μg), UAS-luciferase reporter plasmid (5 μg), Fugene (3:1 ratio; 27μL) and serum-free media (210 μL). The transfection mixture is incubatedfor 20 minutes at room temperature. The cells are harvested by washingwith PBS (30 mL) and then dissociated using trypsin (0.05%; 3 mL). Thetrypsin is inactivated by the addition of assay media (DMEM,lipoprotein-deficient fetal bovine serum (5%), statin (e.g. lovastatin7.5 μM), and mevalonic acid (100 μM)) (10 mL). The cells are countedusing a 1:10 dilution and the concentration of cells adjusted to 160,000cells/mL. The cells are mixed with the transfection mixture (10 mL ofcells per 250 μl of transfection mixture) and are further incubated for30 minutes at room temperature with periodic mixing by inversion. Cells(50 μl/well) are then plated into 384 white, solid-bottom, TC-treatedplates. The cells are further incubated at 37° C., 5.0% CO₂ for 24hours. A 12-point series of dilutions (half-log serial dilutions) areprepared for each test compound in DMSO with a starting concentration ofcompound of 1 μM. Test compound (500n1) is added to each well of cellsin the assay plate and the cells are incubated at 37° C., 5.0% CO₂ for24 hours. The cell lysis/luciferase assay buffer Bright-Glo™ (25%; 25μl; Promega), is added to each well. After a further incubation for 5minutes at room temperature, the luciferase activity is measured.

Raw luminescence values are normalized by dividing them by the value ofthe DMSO control present on each plate. Normalized data is visualizedusing XLfit3 and dose-response curves are fitted using a 4-parameterlogistic model or sigmoidal single-site dose-response equation (equation205 in XLfit3.05). EC50 is defined as the concentration at which thecompound elicits a response that is half way between the maximum andminimum values. Relative efficacy (or percent efficacy) is calculated bycomparison of the response elicited by the compound with the maximumvalue obtained for the known LXR modulator,(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-aceticacid.

Assay 2 Method for Assessing Endogenous Gene Expression Induced by LXRModulator ABCA1 Gene Expression

Human THP1 cells are grown in propagation media (10% defined FBS, 2 mML-glutamine, 10 mM HEPES, 1.0 mM sodium pyruvate, 4.5 g/L glucose, 1.5g/L bicarbonate, 0.05 mM 2-Mercaptoethanol in RPMI 1640). On day 1, 0.5mL of cells at a concentration of 250,000 cells/mL in propagation mediaplus 40 ng/mL PMA are plated per well on a 48-well dish. Plate isincubated for 24 hours at 37 degrees celsius. On day 2, media isreplaced with 0.5 mL fresh assay media (same as propagation media butwith 2% lipoprotein deficient FBS as the serum supplement) and compoundsare added 6 hours later (1 or 10 μM in DMSO). Plate is then incubated at37 degrees for 24 hours. On day 3, cells are harvested and RNA isisolated using the RNeasy kit (Qiagen) with DNaseI option. RNA is elutedin 100 ul of water, quantitated (UV absorbance at 260 nm) and stored at−80 degrees till use.

ABCA1 gene expression is measured using TaqMan quantitative PCR usingthe following primers/probe set for human ABCA1, forward5′TGTCCAGTCCAGTAATGGTTCTGT3′ (SEQ ID NO. 1), reverse5′AAGCGAGATATGGTCCGGATT3′(SEQ ID NO. 2), probe 5′FAMACACCTGGAGAGAAGCTTTCAACGAGACTAACCTAMRA3′ (SEQ ID NO. 3), and human 36B4,forward 5′CCACGCTGCTGAACATGC3′ (SEQ ID NO. 4), reverse5′TCGAACACCTGCTGGATGAC3′ (SEQ ID NO. 5), probe 5′VICAACATCTCCCCCTTCTCCTTTGGGCT TAMRA3′ (SEQ ID NO. 6). Reverse transcriptionand PCR reactions are run in sequence in the same sample mixture usingthe Superscript Platinum III Q-PCR reagent (Invitrogen). Reaction mixes(Superscript RT/platinum Taq—0.4 μl, 2× Reaction Mix—10 μl, 36B4primers—0.4 μl of 10 μM stock, ABCA1 primers—1.8 μl of 10 μM stock,ABCA1 probe-FAM—0.04 μl of 100 μM stock, 36B4 probe-VIC—0.04 μl of 50 μMstock, RNA (50 ng/μl)—2 μl, 50×ROX dye—0.4 μl, MgSO4-0.4 μl of 50 mMstock, water—4.52 μl) are placed in a 384-well plate and run on an ABIHT7900 machine using standard conditions. ABCA1 gene expression isevaluated in reference to a curve of diluted RNA, and normalized to thelevels of 36B4 RNA present in the sample. Fold induction induced bycompound is calculated in reference to DMSO. Relative efficacy (orpercent efficacy) is calculated by comparison of the response elicitedby the compound with the maximum value obtained for the known LXRmodulator,(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-aceticacid.

Fas Gene Expression

Human HepG2 cells are grown in propagation media (10% FBS, 2 mML-glutamine, 1.5 g/L bicarbonate, 0.1 mM non-essential amino acids, 1.0mM sodium pyruvate in DMEM). On day 1, 0.5 mL of cells in propagationmedia at a concentration of 150,000 cells/mL are plated per well on a48-well plate. Plate is then incubated at 37 degrees for 24 hours. Onday 2, media is changed to 0.5 mL of assay media (same as propagationmedia but with 2% lipoprotein deficient FBS as the serum supplement) andcompounds are added 6 hours later (1 or 10 μM in DMSO). Plate is thenincubated at 37 degrees for 36-48 hours. Cells are harvested and RNA isisolated using the RNeasy kit (Qiagen) with DNaseI option. RNA is elutedin 100 ul of water, quantitated (UV absorbance at 260 nm) and stored at−80 degrees till use. Fas gene expression is measured using TaqManquantitative PCR using the following primers/probe set for human Fas,forward 5′GCAAATTCGACCTTTCTCAGAAC3′ (SEQ ID NO. 7), reverse5′GGACCCCGTGGAATGTCA3′ (SEQ ID NO. 8), probe 5′FAMACCCGCTCGGCATGGCTATCTTC TAMRA3′ (SEQ ID NO. 9) and human 36B4, forward5′CCACGCTGCTGAACATGC3′ (SEQ ID NO. 10), reverse 5′TCGAACACCTGCTGGATGAC3′(SEQ ID NO. 11), probe 5′VIC AACATCTCCCCCTTCTCCTTTGGGCTTAMRA3′ (SEQ IDNO. 12). Reverse transcription and PCR reactions are run in sequence inthe same sample mixture using the Superscript Platinum III Q-PCR reagent(Invitrogen). Reaction mixes (Superscript RT/platinum Taq—0.4 μl, 2×Reaction Mix—10 μl, 36B4 primers—1.2 μl of 10 μM stock, Fas primers—1.2μl of 10 μM stock, Fas probe-FAM—0.045 μl of 100 μM stock, 36B4probe-VIC −0.08 μl of 50 μM stock, RNA (50 ng/μl)—2 μl, 50×ROX dye—0.4μl, MgSO4-1 μl of 50 mM stock, water—3.68 μl) are placed in a 384-wellplate and run on an ABI HT7900 machine with standard conditions. Fasgene expression is evaluated in reference to a curve of diluted RNA, andnormalized to the levels of 36B4 RNA present in the sample. Foldinduction induced by compound is calculated in reference to DMSO.

Assay 3 FRET Co-Activator Recruitment Assay

A FRET assay is used to assess the ability of a compound of theinvention to bind directly to the LXR ligand-binding domain (LBD) andpromote the recruitment of proteins that potentiate the transcriptionalactivity of LXRs (e.g. co-activators). This cell-free assay uses arecombinant fusion protein composed of the LXR LBD and a tag (e.g. GST,H is, FLAG) that simplifies its purification, and a syntheticbiotinylated peptide derived from the nuclear receptor interactingdomain of a transcriptional co-activator protein, such as steroidreceptor co-activator 1 (SRC-1). In one format, the tagged LBD fusionprotein can be labeled using an antibody against the LBD tag coupled toeuropium (e.g. EU-labeled anti-GST antibody), and the co-activatorpeptide can be labeled with allophycocyanin (APC) coupled tostreptavidin. In the presence of an agonist for LXR, the co-activatorpeptide is recruited to the LXR LBD, bringing the EU and APC moieties inclose proximity. Upon excitation of the complex with light at 340 nM, EUabsorbs and transfers energy to the APC moiety resulting in emission at665 nm. If there is no energy transfer (indicating lack of EU-APCproximity), EU emits at 615 nm. Thus the ratio of the 665 to 615 nmlight emitted gives an indication of the strength of co-activatorpeptide recruitment, and thus of agonist binding to the LXR LBD.

Fusion proteins, amino acids 205-447 (Genbank NM_(—)005693) for LXRα(NR1H3) and amino acids 203-461 (NM_(—)007121 for β) for LXRβ (NR1H3),were cloned in-frame at the Sal1 and Not1 sites of pGEX4T-3 (27-4583-03Amersham Pharmacia Biotech). A biotinylated peptide sequence was derivedfrom SRC-1 (amino acids 676 to 700):biotin-CPSSHSSLTERHKILHRLLQEGSPSC-OH (SEQ ID NO. 13).

A master mix is prepared (5 nM GST-LXR-LBD, 5 nM Biotinylated SRC-1peptide, 10 nM APC-Streptavidin (Prozyme Phycolink streptavidin APC,PJ25S), and 5n MEU-Anti-GST Antibody) in FRET buffer (50 mM Tris pH 7.5,50 mM KCl 1 mM DTT, 0.1% BSA). To each well of a 384 well plate, 20 μLof this master mix is added. Final FRET reaction: 5 nM fusion protein, 5nM SRC-1 peptide, 10 nM APC-Streptavidin, 5 nm EU-Anti-GST Antibody(PerkinElmer AD0064). Test compounds are diluted in half-log, 12-pointserial dilutions in DMSO, starting at 1 mM and 100 mL of compound istransferred to the master mix for a final concentration of 5 μM-28 pM inthe assay wells. Plates are incubated at room temperature for 3 hoursand fluorescence resonance energy transfer read. Results are expressedas the ratio of APC fluorescence to EU fluorescence times one thousand.

The ratio of 665 nm to 615 nm is multiplied by a factor of 1000 tosimplify data analysis. DMSO values are subtracted from ratios toaccount for background. Data is visualized using XLfit3 anddose-response curves are fitted using a 4-parameter logistic model orsigmoidal single-site dose-response equation (equation 205 inXLfit3.05). EC50 is defined as the concentration at which the compoundelicits a response that is half way between the maximum and minimumvalues. Relative efficacy (or percent efficacy) is calculated bycomparison of the response elicited by the compound with the maximumvalue obtained for a reference LXR modulator.

Compounds of Formula I, in free form or in pharmaceutically acceptablesalt form, exhibit valuable pharmacological properties, for example, asindicated by the in vitro tests described in this application. Compoundsof the invention display % Efficacy for expression of endogenous ABCA1ranging from 10% to 130%. It is understood that the examples andembodiments described herein are for illustrative purposes only and thatvarious modifications or changes in light thereof will be suggested topersons skilled in the art and are to be included within the spirit andpurview of this application and scope of the appended claims. Allpublications, patents, and patent applications cited herein are herebyincorporated by reference for all purposes.

1. A compound of Formula I:

in which n is selected from 0, 1, 2 and 3; Z is selected from C andS(O); each Y is independently selected from —CR₄═ and —N═; wherein R₄ isselected from hydrogen, cyano, hydroxyl, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy; R₁ isselected from halo, cyano, hydroxyl, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy and —C(O)OR₄;wherein R₄ is as described above; R₂ is selected from C₆₋₁₀aryl,C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl and C₃₋₈heterocycloalkyl; wherein anyaryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₂ is optionallysubstituted with 1 to 5 radicals independently selected from halo,hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —C(O)NR₅R₅,—OR₅, —OC(O)R₅, —NR₅R₆, —C(O)R₅ and —NR₅C(O)R₅; wherein R₅ and R₆ areindependently selected from hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,C₆₋₁₀aryl-C₀₋₄alkyl, C₃₋₈heteroaryl-C₀₋₄alkyl,C₃₋₁₂cycloalkyl-C₀₋₄-alkyl and C₃₋₈heterocycloalkyl-C₀₋₄alkyl; or R₅ andR₆ together with the nitrogen atom to which R₅ and R₆ are attached formC₅₋₁₀heteroaryl or C₃₋₈heterocycloalkyl; wherein any aryl, heteroaryl,cycloalkyl or heterocycloalkyl of R₅ or the combination of R₅ and R₆ isoptionally substituted with 1 to 4 radicals independently selected fromhalo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy; R₃ isselected from C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl andC₃₋₈heterocycloalkyl; wherein any aryl, heteroaryl, cycloalkyl orheterocycloalkyl of R₃ is substituted with 1 to 5 radicals independentlyselected from halo, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl,halo-substituted-C₁₋₆alkoxy, —OXR₇, —OXC(O)NR₇R₈, —OXC(O)NR₇XC(O)OR₈,—OXC(O)NR₇XOR₈, —OXC(O)NR₇XNR₇R₈, —OXC(O)NR₇XS(O)₀₋₂R₈,—OXC(O)NR₇XNR₇C(O)R₈, —OXC(O)NR₇XC(O)XC(O)OR₈, —OXC(O)NR₇R₉, —OXC(O)OR₇,—OXOR₇, —OXR₉, —XR₉, —OXC(O)R₉, —OXS(O)₀₋₂R₉ and —OXC(O)NR₇CR₇[C(O)R₈]₂;wherein X is a selected from a bond and C₁₋₆alkylene wherein anymethylene of X can optionally be replaced with a divalent radicalselected from C(O), NR₇, S(O)₂ and O; R₇ and R₈ are independentlyselected from hydrogen, cyano, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl,C₂₋₆alkenyl and C₃₋₁₂cycloalkyl-C₀₋₄alkyl; R₉ is selected fromC₆₋₁₀aryl-C₀₋₄ alkyl, C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₂cycloalkyl-C₀₋₄alkyl and C₃₋₈heterocycloalkyl-C₀₋₄alkyl; wherein any alkyl of R₉ canhave a hydrogen replaced with —C(O)OR₁₀; and any aryl, heteroaryl,cycloalkyl or heterocycloalkyl of R₉ is optionally substituted with 1 to4 radicals independently selected from halo, C₁₋₆alkyl, C₃₋₁₂cycloalkyl,halo-substituted-C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-substituted-C₁₋₆ alkoxy,—XC(O)OR₁₀, —XC(O)R₁₀, —XC(O)NR₁₀R₁₀, —XS(O)₀₋₂NR₁₀R₁₀ and —XS(O)₀₋₂R₁₀;wherein R₁₀ is independently selected from hydrogen and C₁₋₆alkyl; andthe pharmaceutically acceptable salts, hydrates, solvates and isomersthereof.
 2. The compound of claim 1 of Formula Ia:

in which n is selected from 1, 2 and 3; Y is selected from —CH═ and —N═;R₁ is selected from halo, C₁₋₆alkyl, and —C(O)OR₄; wherein R₄ isselected from hydrogen and C₁₋₆alkyl; R₂ is selected from C₆₋₁₀aryl,C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl and C₃₋₈heterocycloalkyl; wherein anyaryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₂ is optionallysubstituted with 1 to 4 radicals independently selected from halo,hydroxy, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl and —OC(O)R₅; wherein R₅is selected from hydrogen and C₁₋₆alkyl; and R₃ is selected fromC₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl and C₃₋₈heterocycloalkyl;wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₃ issubstituted with 1 to 5 radicals independently selected from halo,hydroxyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl,halo-substituted-C₁₋₆alkoxy, —OXR₇, —OXC(O)NR₇R₈, —OXC(O)NR₇XC(O)OR₈,—OXC(O)NR₇XOR₈, —OXC(O)NR₇XNR₇R₈, —OXC(O)NR₇XS(O)₀₋₂R₈,—OXC(O)NR₇XNR₇C(O)R₈, —OXC(O)NR₇XC(O)XC(O)OR₈, —OXC(O)NR₇R₉, —OXC(O)OR₇,—OXOR₇, —OXR₉, —XR₉, —OXC(O)R₉ and —OXC(O)NR₇CR₇[C(O)R₈]₂; wherein X isa selected from a bond and C₁₋₆alkylene; R₇ and R₈ are independentlyselected from hydrogen, cyano, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl,C₂₋₆alkenyl and C₃₋₁₂cycloalkyl-C₀₋₄alkyl; R₉ is selected fromC₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl-C₀₋₄alkyl,C₃₋₁₂cycloalkyl-C₀₋₄-alkyl and C₃₋₈heterocycloalkyl-C₀₋₄alkyl; whereinany alkyl of R₉ can have a hydrogen replaced with —C(O)OR₁₀; and anyaryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₉ is optionallysubstituted with 1 to 4 radicals independently selected from halo,C₁₋₆alkyl, C₃₋₁₂cycloalkyl, halo-substituted-C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkoxy, —XC(O)OR₁₀, —XC(O)R₁₀,—CR₁₀(NR₁₀R₁₀)═NOR₁₀, —XC(O)NR₁₀R₁₀, —XS(O)₀₋₂NR₁₀R₁₀ and —XS(O)₀₋₂R₁₀;wherein R₁₀ is independently selected from hydrogen and C₁₋₆alkyl. 3.The compound of claim 2 in which R₁ is selected from fluoro, chloro,methyl and —C(O)OCH₃; and R₂ is selected from phenyl, cyclohexyl,cyclopentyl, pyrrolyl, pyrazolyl, naphthyl, benzo[1,3]dioxolyl, thienyl,furanyl and pyridinyl; wherein any aryl, heteroaryl or cycloalkyl of R₂is optionally substituted with 1 to 4 radicals independently selectedfrom fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, t-butyl,amino, dimethyl-amino, methoxy, trifluoromethyl, trifluoromethoxy and—OC(O)CH₃.
 4. The compound of claim 3 in which R₃ is selected fromphenyl, benzo[1,3]dioxolyl, pyridinyl,2,2-difluoro-benzo[1,3]dioxol-5-yl and benzooxazolyl; wherein any arylor heteroaryl of R₃ is substituted with 1 to 5 radicals independentlyselected from fluoro, chloro, bromo, methoxy, hydroxyl, difluoromethoxy,—OCH₂C(O)NH₂, —OCH₂C(O)OCH₃, —OCH₂C(O)NHCH₃, —OCH₂C(O)N(CH₃)₂, —R₉,—OR₉, —OCH₂R₉, —OCH₂C(O)R₉, —OCH₂C(O)NHR₉, —OCH₂C(O)N(CH₃)R₉,—OCH₂C(O)NHCH₂R₉, —OCH₂CN, —OCH₂C₂H₃, —OCH₂C₂H₄, —O(CH₂)₂OH,—OCH₂C(O)NH(CH₂)₂C(O)OC₂H₅, —OCH₂C(O)NH(CH₂)₂CH₂F, —OCH₂C(O)NHCH₂CH₂F,—OCH₂C(O)NH(CH₂)₂C(O)OH, —OCH₂C(O)NHCH(CH₂R₉)C(O)OC₂H₅,—OCH₂C(O)NHC(O)(CH₂)₂C(O)OCH₃, —OCH₂C(O)NH(CH₂)₂NHC(O)CH₃,—OCH₂C(O)NHCH₂C(O)C₂H₅, OCH₂C(O)NH(CH₂)₂C(O)OC₄H₉,—OCH₂C(O)NHCH₂C(O)OC₂H₅, OCH₂C(O)NHCH[C(O)OC₂H₅]₂, —S(O)₂CH₃,—OCH₂C(O)NHCH₂CF₃, OCH₂C(O)NHCH₂C(O)(CH₂)₂C(O)OCH₃,—OCH₂C(O)N(CH₃)CH₂C(O)OCH₃, OCH₂C(O)NH(CH₂)₃OC₂H₅,—OCH₂C(O)NH(CH₂)₃OCH(CH₃)₂, OCH₂C(O)NH(CH₂)₂SCH₃,—OCH₂C(O)NHCH₂CH(CH₃)₂, OCH₂C(O)NHCH(CH₃)CH₂OH,—OCH₂C(O)NHCH₂CH(CH₃)C₂H₅, OCH₂C(O)NHCH(CH₃)C(O)OC₂H₅,—OCH₂C(O)NHCH₂CH(CH₃)₂ and OCH₂C(O)(CH₂)₃OCH(CH₃)₂; wherein R₉ isphenyl, cyclopropyl-methyl, isoxazolyl, benzthiazolyl, furanyl,furanyl-methyl, tetrahydro-furanyl, pyridinyl,4-oxo-4,5-dihydro-thiazol-2-yl, pyrazolyl, isothiazolyl,1,3,4-thiadiazolyl, thiazolyl, phenethyl, morpholino, morpholino-propyl,isoxazolyl-methyl, pyrimidinyl, tetrahydro-pyranyl,2-oxo-2,3-dihydro-pyrimidin-4-yl, piperazinyl, pyrrolyl, piperidinyl,pyrazinyl, imidazolyl, imidazolyl-propyl, benzo[1,3]dioxolyl,benzo[1,3]dioxolyl-propyl, 2-oxo-pyrrolidin-1-yl and2-oxo-pyrrolidin-1-yl-propyl; wherein any alkyl of R₉ can have ahydrogen replaced with —C(O)OC₂H₅; wherein any aryl, heteroaryl orheterocycloalkyl of R₉ is optionally substituted with 1 to 4 radicalsindependently selected from methyl, ethyl, cyclopropyl, methoxy,trifluoromethyl, —OC(O)CH₃, —COOH, —S(O)₂NH₂, —CH(NH₂)═NOH, —C(O)OC₂H₅,—CH₂C(O)OH, —CH₂C(O)OC₂H₅, —CH₂C(O)OCH₃, —C(O)OCH₃, —C(O)NH₂, —C(O)NHCH₃and —C(O)CH₃.
 5. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1 in combinationwith a pharmaceutically acceptable excipient.
 6. A method for treating adisease or disorder in an animal in which modulation of LXR activity canprevent, inhibit or ameliorate the pathology and/or symptomatology ofthe disease, which method comprises administering to the animal atherapeutically effective amount of a compound of claim
 1. 7. The methodof claim 6 wherein the diseases or disorder are selected fromcardiovascular disease, diabetes, neurodegenerative diseases andinflammation.
 8. The use of a compound of claim 1 in the manufacture ofa medicament for treating a disease or disorder in an animal in whichLXR activity contributes to the pathology and/or symptomatology of thedisease, said disease being selected from cardiovascular disease,diabetes, neurodegenerative diseases and inflammation.
 9. A method fortreating a disease or disorder in an animal in which modulation of LXRactivity can prevent, inhibit or ameliorate the pathology and/orsymptomatology of the disease, which method comprises administering tothe animal a therapeutically effective amount of a compound of claim 1.10. The method of claim 9 further comprising administering atherapeutically effective amount of a compound of claim 1 in combinationwith another therapeutically relevant agent.